Pyrazolopyridines and pyrazolopyridazines as antidiabetics

ABSTRACT

The present invention includes compound of formula (I), 
                         
or a derivative thereof, wherein Y is CH or N; R 1  is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, aralkyl wherein the aryl and the alkyl moieties may each independently be unsubstituted or substituted, aralkenyl wherein the aryl, and alkenyl moieties may each independently be unsubstituted or substituted, unsubstituted or substituted heterocyclyl, or heterocyclylalkyl wherein the heterocyclyl and the alkyl moieties may each independently be unsubstituted or substituted; and R 2  is unsubstituted aryl or unsubstituted or substituted or substituted heteroaryl. Additionally the present invention includes a process for preparing such a compound, a pharmaceutical composition containing such a compound, and the use of such a compound in medicine.

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/GB01/04186 filed Sep. 19, 2001, which claims priority from 0023358.5filed Sep. 22, 2000; 0023361.9 filed Sep. 22, 2000; 0107391.5 filed Mar.23, 2001; 0110671.5 filed May 1, 2001; 0112799.2 filed May 25, 2001.

This invention relates to novel compounds, in particular to novelpyrazolopyridine and pyrazolopyridazine derivatives, to processes forthe preparation of such compounds, to pharmaceutical compositionscontaining such compounds and to the use of such compounds in medicine.

GSK-3 is a serine/threonine protein kinase composed of two isoforms (αand β) which are encoded by distinct genes. GSK-3 is one of severalprotein kinases which phosphorylates glycogen synthase (GS) (Embi et alEur. J. Biochem. (107) 519–527 (1980)). The α and β isoforms have amonomeric structure and are both found in mammalian cells. Both isoformsphosphorylate muscle glycogen synthase (Cross et al Biochemical Journal(303) 21–26 (1994)) and these two isoforms show good homology betweenspecies (e.g. human and rabbit GSK-3α are 96% identical).

Type II diabetes (or Non-Insulin Dependent Diabetes Mellitus, NIDDM) isa multifactorial disease. Hyperglycaemia is due to insulin resistance inthe liver, muscle and other tissues coupled with inadequate or defectivesecretion of insulin from pancreatic islets. Skeletal muscle is themajor site for insulin-stimulated glucose uptake and in this tissue,glucose removed from the circulation is either metabolised throughglycolysis and the TCA cycle, or stored as glycogen. Muscle glycogendeposition plays the more important role in glucose homeostasis and TypeII diabetic subjects have defective muscle glycogen storage.

The stimulation of glycogen synthesis by insulin in skeletal muscleresults from the dephosphorylation and activation of glycogen synthase(Villar-Palasi C. and Lamer J. Biochimn. Biophys. Acta (39) 171–173(1960), Parker P J et al., Eur. J. Biochem. (130) 227–234 (1983), andCohen P. Biochem. Soc. Trans. (21) 555–567 (1993)). The phosphorylationand dephosphorylation of GS are mediated by specific kinases andphosphatases. GSK-3 is responsible for phosphorylation and deactivationof GS, while glycogen bound protein phosphatase 1 (PP1G)dephosphorylates and activates GS. Insulin both inactivates GSK-3 andactivates PP1G (Srivastava A K and Pandey S K Mol. and Cellular Biochem.(182) 135–141 (1998)).

Chen et al Diabetes (43) 1234–1241 (1994) found that there was nodifference in the mRNA abundance of PP1G between patients with Type IIdiabetes and control patients, suggesting that an increase in GSK-3activity might be important in Type II diabetes. It has also recentlybeen demonstrated that GSK-3 is overexpressed in Type II diabetic muscleand that an inverse correlation exists between skeletal muscle GSK-3αactivity and insulin action (Nikoulina et al Diabetes 2000, 49 263–271).Overexpression of GSK-3β and constitutively active GSK-3β (S9A, S9E)mutants in HEK-293 cells resulted in suppression of glycogen synthaseactivity (Eldar-Finkelman et al., PNAS (93) 10228–10233 (1996)) andoverexpression of GSK-3β in CHO cells, expressing both insulin receptorand insulin receptor substrate 1 (IRS-1), resulted in an impairment ofinsulin action (Eldar-Finkelman and Krebs PNAS (94) 9660–9664 (1997)).Recent evidence for the involvement of elevated GSK-3 activity and thedevelopment of insulin resistance and type II diabetes in adipose tissuehas emerged from studies undertaken in diabetes and obesity proneC57BL/6J mice (Eldar-Finkelman et al., Diabetes (48) 1662–1666 (1999)).

GSK-3 has been shown to phosphorylate other proteins in vitro includingthe eukaryotic initiation factor eIF-2B at Serine⁵⁴⁰ (Welsh et al., FEBSLetts (421) 125–130 (1998)). This phosphorylation results in aninhibition of eIF-2B activity and leads to a reduction in this keyregulatory step of translation. In disease states, such as diabetes,where there is elevated GSK-3 activity this could result in a reductionof translation and potentially contribute to the pathology of thedisease.

Several aspects of GSK-3 functions and regulation in addition tomodulation of glycogen synthase activity indicate that inhibitors ofthis enzyme may be effective in treatment of disorders of the centralnervous system. GSK-3 activity is subject to inhibitory phosphorylationby PI 3 kinase-mediated or Wnt-1 class-mediated signals that can bemimicked by treatment with lithium, a low mM inhibitor of GSK-3(Stambolic V., Ruel L. and Woodgett J. R Curr. Biol. 1996 6(12):1664–8).

GSK-3 inhibitors may be of value as neuroprotectants in treatment ofacute stroke and other neurotraumatic injuries. Roles for PI 3-kinasesignalling through PKB/akt to promote neuronal cell survival are wellestablished, and GSK-3 is one of a number of PKB/akt substrates to beidentified that can contribute to the inhibition of apoptosis via thispathway (Pap & Cooper, (1998) J. Biol. Chem. 273: 19929–19932). Evidencesuggests that astrocytic glycogen can provide an alternative energysource to facilitate neuronal survival under conditions of glucosedeprivation (for example see Ransom, B. R. and Fern, R. (1997) Glia 21:134–141 and references therein). Lithium is known to protect cerebellargranule neurons from death (D'Mello et al., (1994) Exp. Cell Res. 211:332–338 and Volonte et al (1994) Neurosci. Letts. 172: 6–10) and chroniclithium treatment has demonstrable efficacy in the middle cerebralartery occlusion model of stroke in rodents (Nonaka and Chuang, (1998)Neuroreport 9(9): 2081–2084). Wnt-induced axonal spreading and branchingin neuronal culture models has been shown to correlate with GSK-3inhibition (Lucas & Salinas, (1997) Dev. Biol. 192: 31–44) suggestingadditional value of GSK-3 inhibitors in promoting neuronal regenerationfollowing neurotraumatic insult.

Tau and β-catenin, two known in vivo substrates of GSK-3, are of directrelevance in consideration of further aspects of the value of GSK-3inhibitors in relation to treatment of chronic neurodegenerativeconditions. Tau hyperphosphorylation is an early event inneurodegenerative conditions such as Alzheimer's disease (AD), and ispostulated to promote microtubule disassembly. Lithium has been reportedto reduce the phosphorylation of tau, enhance the binding of tau tomicrotubules, and promote microtubule assembly through direct andreversible inhibition of glycogen synthase kinase-3 (Hong M., Chen D.C., Klein P. S. and Lee V. M. J. Biol. Chem. 1997 272(40) 25326–32).β-catenin is phosphorylated by GSK-3 as part of a tripartite complexwith axin, resulting in β-catenin being targetted for degradation (Ikedaet al., (1998) EMBO J. 17: 1371–1384). Inhibition of GSK-3 activity is akey mechanism by which cytosolic levels of catenin are stabilised andhence promote β-catenin-LEF-1/TCF transcriptional activity (Eastman,Grosschedl (1999) Curr. Opin. Cell Biol. 11: 233). Rapid onset ADmutations in presenilin-1 (PS-1) have been shown to decrease thecytosolic β-catenin pool in transgenic mice. Further evidence suggeststhat such a reduction in available β-catenin may increase neuronalsensitivity to amyloid mediated death through inhibition ofβ-catenin-LEF-1/TCF transcriptional regulation of neuroprotective genes(Zhang et al., (1998) Nature 395: 698–702). A likely mechanism issuggested by the finding that mutant PS-1 protein confers decreasedinactivation of GSK-3 compared with normal PS-1 (Weihl, C. C., Ghadge,G. D., Kennedy, S. G., Hay, N., Miller, R. J. and Roos, R. P. (1999) J.Neurosci. 19: 5360–5369).

International Patent Application Publication Number WO 97/41854(University of Pennsylvania) discloses that an effective drug for thetreatment of manic depression is lithium, but that there are seriousdrawbacks associated with this treatment. Whilst the precise mechanismof action of this drug for treatment of bipolar disorder remains to befully defined, current models suggest that inhibition of GSK-3 is arelevant target that contributes to the modulation of AP-1 DNA bindingactivity observed with this compound (see Manji et al., (1999) J. Clin.Psychiatry 60 (suppl 2): 27–39 for review).

GSK-3 inhibitors may also be of value in treatment of schizophrenia.Reduced levels of β-catenin have been reported in schizophrenic patients(Cotter D, Kerwin R, al-Sarraji S, Brion J P, Chadwich A, Lovestone S,Anderton B, and Everall I. 1998 Neuroreport 9:1379–1383 ) and defects inpre-pulse inhibition to startle response have been observed inschizophrenic patients (Swerdlow et al (1994) Arch. Gen. Psychiat. 51:139–154). Mice lacking the adaptor protein dishevelled-1, an essentialmediator of Wnt-induced inhibition of GSK-3, exhibit both a behaviouraldisorder and defects in pre-pulse inhibition to startle response (LijamN, Paylor R, McDonald M P, Crawley J N, Deng C X, Herrup K, Stevens K E,Maccaferri G, McBain C J, Sussman D J, and Wynshaw-Boris A. (1997) Cell90: 895–905). Together, these findings implicate deregulation of GSK-3activity as contributing to schizophrenia. Hence, small moleculeinhibitors of GSK-3 catalytic activity may be effective in treatment ofthis mood disorder.

The finding that transient β-catenin stabilisation may play a role inhair development (Gat et al Cell (95) 605–614(1998)) suggests that GSK-3inhibitors could be used in the treatment of baldness.

Studies on fibroblasts from the GSK-3β knockout mouse (Hoeflich K P etal., Nature 2000, 406, 86–90) support a role for this kinase inpositively regulating the activity of NFkB. This transcription factormediates cellular responses to a number of inflammatory stimuli.Therefore, pharmacologic inhibition of GSK-3 may be of use in treatinginflammatory disorders through the negative regulation of NFkB activity.

We have now discovered that a series of pyrazolo[3,4-b]pyridines andpyrazolo[3,4-c]pyridazines are particularly potent and selectiveinhibitors of GSK-3. These compounds are indicated to be useful for thetreatment and/or prophylaxis of conditions associated with a need forinhibition of GSK-3, such as diabetes, conditions associated withdiabetes, chronic neurodegenerative conditions including dementias suchas Alzheimers disease, Parkinson's disease, progressive supranuclearpalsy, subacute sclerosing panencephalitic parkinsonism,postencephalitic parkinsonism, pugilistic encephalitis, guamparkinsonism-dementia complex, Pick's disease, corticobasaldegeneration, frontotemporal dementia, Huntingdon's disease, AIDSassociated dementia, amyotrophic lateral sclerosis, multiple sclerosisand neurotraumatic diseases such as acute stroke, mood disorders such asschizophrenia and bipolar disorders, promotion of functional recoverypost stroke, cerebral bleeding (for example, due to solitary cerebralamyloid angiopathy), hair loss, obesity, atherosclerotic cardiovasculardisease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia,traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy bodydisease, inflammation, and immunodeficiency.

Accordingly, in a first aspect, the present invention provides acompound of formula (I),

or a derivative thereof,wherein;

Y is CH or N;

R¹ is unsubstituted or substituted alky, unsubstituted or substitutedcycloalkyl, unsubstituted or substituted alkenyl, unsubstituted orsubstituted cycloalkenyl, unsubstituted or substituted aryl, aralkylwherein the aryl and the alkyl moieties may each independently beunsubstituted or substituted, aralkenyl wherein the aryl and alkenylmoieties may each independently be unsubstituted or substituted,unsubstituted or substituted heterocyclyl, or heterocyclylalkyl whereinthe heterocyclyl and the alkyl moieties may each independently beunsubstituted or substituted;

R² is unsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl.

Suitably, Y is CH. Suitably, Y is N.

Preferably, R¹ is unsubstituted or substituted alkyl, unsubstituted orsubstituted cycloalkyl, unsubstituted or substituted alkenyl,unsubstituted or substituted aryl, aralkyl wherein the aryl and thealkyl moieties may each independently be unsubstituted or substituted,aralkenyl wherein the aryl and alkenyl moieties may each independentlybe unsubstituted or substituted, unsubstituted or substitutedheterocyclyl, and heterocyclylalkyl wherein the heterocyclyl and thealkyl moieties may each independently be unsubstituted or substituted.

When R¹ is unsubstituted or substituted alkyl, examples includeC₁₋₆alkyl, for example methyl, ethyl, propyl, iso-propyl, butyl, pentyland hexyl.

When R¹ is unsubstituted or substituted cycloalkyl, examples includecycloC₃₋₈alkyl, for example cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

When R¹ is unsubstituted or substituted alkenyl, examples includeC₂₋₆alkenyl, for example propenyl and butenyl.

When R¹ is unsubstituted or substituted cycloalkenyl, examples includecycloC₃₋₈alkenyl.

When R¹ is unsubstituted or substituted aryl, examples include phenyland naphthalenyl.

When R¹ is unsubstituted or substituted aralkyl, examples includearylC₁₋₆ alkyl, for example benzyl and phenethyl.

When R¹ is unsubstituted or substituted aralkenyl, examples includearylC₂₋₆alkenyl, for example phenethenyl.

When R¹ is unsubstituted or substituted heterocyclyl, examples includeC₃₋₇heterocyclyl, for example furyl, pyridinyl, piperidinyl,pyrrolidinyl, benzodioxalanyl, thienyl and dihydrobenzofuranyl. When R¹is unsubstituted or substituted heterocyclylalkyl, examples includeC₃₋₇heterocyclylC₁₋₆alkyl, for example piperindinylmethyl,piperidinylpropyl, piperazinylpropyl, piperazinylbutyl,morpholinylpropyl, pyridinylethyl, pyridinylmethyl, pyrrolidinylpropyl,(1-pyridinium)butyl bromide salt, thiomorpholinylpropyl,(1-oxo-thiomorpholinyl)propyl, (1,1-dioxo-thiomorpholinyl)propyl andpiperidinylbutyl.

When R¹ is substituted alkyl, suitable substituents include halo,C₁₋₆alkoxy, carboxy, di(C₁₋₆alkyl)amino, C₁₋₆alkoxyC₂₋₆alkoxy,haloC₁₋₆alkoxy, aryloxy such as phenoxy,C₁₋₆alkoxyC₂₋₆alkyl(C₁₋₆alkyl)amino, di(C₁₋₆alkoxyC₂₋₆alkyl)amino.

When R¹ is substituted cycloalkyl, suitable substituents include up tofive groups independently selected from the list consisting of hydroxy,C₁₋₆alkoxy, di(C₁₋₆alkyl)amino, cyano, C₁₋₆alkyl, carboxy,C₁₋₆alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, C₁₋₆alkylcarbonylamino,amino, halo and nitro.

When R¹ is substituted alkenyl, suitable substituents include halo,C₁₋₆alkoxy, carboxy, di(C₁₋₆alkyl)amino, C₁₋₆alkoxyC₂₋₆alkoxy,haloC₁₋₆alkoxy, aryloxy such as phenoxy,C₁₋₆alkoxyC₂₋₆alkyl(C₁₋₆alkyl)amino, di(C₁₋₆alkoxyC₂₋₆alkyl)amino.

When R¹ is substituted cycloalkenyl, suitable substituents include up tofive groups independently selected from the list consisting of hydroxy,C₁₋₆alkoxy, di(C₁₋₆alkyl)amino, cyano, C₁₋₆alkyl, carboxy,C₁₋₆alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, C₁₋₆alkylcarbonylamino,amino, halo and nitro.

When R¹ is substituted aryl, suitable substituents include up to fivegroups independently selected from the list consisting of hydroxy,C₁₋₆alkoxy, mono- and di(C₁₋₆alky)amino, cyano, C₁₋₆alkyl, carboxy,C₁₋₆alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, C₁₋₆alkylcarbonylamino,amino, halo and nitro.

When R¹ is substituted heterocyclyl, suitable substituents include up tofive groups independently selected from the list consisting of hydroxy,C₁₋₆alkoxy, mono- and di(C₁₋₆alkyl)amino, cyano, C₁₋₆alkyl, carboxy,C₁₋₆alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, C₁₋₆alkylcarbonylamino,amino, halo and nitro.

When Y is CH or N, suitably R¹ is trifluoromethyl, 2,2,2-trifluoroethyl,methyl, ethyl, n-propyl, n-butyl, 2-butyl, n-pentyl, 3-pentyl, n-hexyl,methoxymethyl, 2-carboxyethyl, n-propenyl, iso-butenyl, styryl, phenyl,2-furyl, 2-thienyl, benzyl, phenylethyl, 3-(N,N-dimethylamino)propyl,pyridin-4-yl, 3-(piperidin-1-yl)propyl, 3-(4-ethylpiperazin-1-yl)propyl,3-(morpholin-4-yl)propyl, 1,3-benzodioxolan-5-yl,N-methylpiperidin-4-yl, iso-propyl, pyridin-3-ylmethyl,α,α-dimethylbenzyl, 3-(meso-3,5-dimethylmorpholin-4-yl)propyl,4-(1-pyridinium)butyl bromide salt, 2-(3-pyridinyl)ethyl, tert-butyl,phenoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,4-dimethylaminobenzyl, 4-(dimethylaminomethyl)benzyl,methoxyethoxymethyl, 2,2,2-trifluoroethoxymethyl,3-dimethylaminophenoxymethyl, (1-methylpiperidin-4-yl)methyl,(1-ethylpiperidin-4-yl)methyl, (1-phenylpiperidin-4-yl)methyl,(1-benzylpiperidin-4-yl)methyl,(1-(4-fluorobenzyl)piperidin-4-yl)methyl,(1-(phenoxyethyl)piperidin-4-yl)methyl, 4-fluorophenethyl,(6-methylpyridn-3-yl)ethyl, methoxyethyl, 3-(N,N-diethylamino)propyl,N-methoxyethyl(N-methyl)aminopropyl, di-(N-methoxyethyl)aminopropyl,3-(1,1-dioxo-1-thiomorpholin-4-yl)propyl, 3-(pyrrolidin-1-yl)propyl,3-(4-benzylpiperazin-1-yl)propyl,3-(4-(4-chlorophenoxy)piperidin-1-yl)propyl,3-(4-methanesulfonylpiperazin-1-yl)propyl, 4-(N,N-diethylamino)butyl,4-(piperidin-1-yl)butyl, piperidin-4-yl, 1-ethylpiperidin-4-yl,1-benzylpiperidin-4-yl, 1-(4-chlorobenzyl)piperidin-4-yl,1-(4-fluorobenzyl)piperidin-4-yl, 1-(methoxyethyl)piperidin-4-yl,1-(phenoxyethyl)piperidin-4-yl, 1-(4-chlorophenoxyethyl)piperidin-4-yl,1-phenylpiperidin-4-yl, 1-benzylpyrrolidin-3-yl, trans-phenethenyl,trans-4-fluorophenethenyl, 4-fluorophenyl, 4-dimethylarinophenyl,2,4,6-trimethylphenyl, 4-(diethylaminomethyl)phenyl,4-(piperidin-1-ylmethyl)phenyl, 4-(pyrolidin-1-ylmethyl)phenyl,4-(thiomorpholin-4-ylmethyl)phenyl, 2,3-dihydrobenzofuran-5-yl,3-(4-(2-phenylethyl)piperazin-1-yl)propyl,3-(4-cyclohexylmethylpiperazin-1-yl)propyl,3-(4-cyclopentylpiperazin-1-yl)propyl,3-(4-iso-propylpiperazin-1-yl)propyl, 3-(4-phenylpiperazin-1-yl)propyl,4-(4-ethylpiperazin-1-yl)butyl, 3-(piperidin-1-ylmethyl)phenyl,4-(diethylaminomethyl)phenyl, 4-(4-ethylpiperazin-1-ylmethyl)phenyl,benzothien-2-yl, 4-methoxybenzyl or benzyloxymethyl.

When Y is CH, preferably R¹ is cyclopropyl, cyclopentyl, cyclobutyl,cyclohexyl, pyridin-3-ylmethyl, 3-pentyl, α,α-dimethylbenzyl, 2-butyl,3-(meso-3,5-dimethylnorpholin-4-yl)propyl, 4-(N,N-diethylamino)butyl,4-(1-pyridinium)butyl bromide salt, trans-phenethenyl,4-dimethylaminophenyl, 1,3-benzodioxolan-5-yl, 2,4,6-trimethylphenyl,2-thienyl, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, methoxymethyl, 2-carboxyethyl,n-propenyl, iso-butenyl, styryl, phenyl, 2-furyl, benzyl, phenylethyl,3-(N,N-dimethylamino)propyl, pyridin-4-yl, 3-(piperidin-1-yl)propyl,3-(4-ethylpiperazin-1-yl)propyl, 3-(morpholin-4-yl)propyl,N-methylpiperidin-4-yl, iso-propyl, 2-(3-pyridinyl)ethyl, tert-butyl, orphenoxymethyl.

When Y is N, preferably R¹ is methyl, n-propyl, iso-propyl, cyclopropyl,cyclopentyl, benzyl, 3-(N,N-dimethylamino)propyl,3-(morpholin-4-yl)propyl, 4-dimethylaminobenzyl,4-(dimethylaminomethyl)benzyl, methoxymethyl, methoxyethoxymethyl,2,2,2-tifluoroethoxymethyl, phenoxymethyl, 3-dimethylaminophenoxymethyl,(1-methylpiperidin-4-yl)methyl, (1-ethylpiperidin-4-yl)methyl,(1-phenylpiperidin-4-yl)methyl, (1-benzylpiperidin-4-yl)methyl,(1-(4-fluorobenzyl)piperidin-4-yl)methyl,(1-(phenoxyethyl)piperidin-4-yl)methyl, phenethyl, 4-fluorophenethyl,(6-methylpyridin-3-yl)ethyl, methoxyethyl, 3-(N,N-diethylamino)propyl,N-methoxyethyl(N-methyl)aminopropyl, di-(N-methoxyethyl)aminopropyl,3-(1,1-dioxo-1-thiomorpholin-4-yl)propyl, 3-(piperidin-1-yl)propyl,3-(pyrrolidin-1-yl)propyl, 3-(4-ethylpiperazin-1-yl)propyl,3-(4-benzylpiperazin-1-yl)propyl,3-(4-(4-chlorophenoxy)piperidin-1-yl)propyl,3-(4-methanesulfonylpiperazin-1-yl)propyl, 4-(N,N-diethylamino)butyl,4-(piperidin-1-yl)butyl, piperidin-4-yl, 1-methylpiperidin-4-yl,1-ethylpiperidin-4-yl, 1-benzylpiperidin-4-yl,1-(4-chlorobenzyl)piperidin-4-yl, 1-(4-fluorobenzyl)piperidin-4-yl,1-(methoxyethyl)piperidin-4-yl, 1-(phenoxyethyl)piperidin-4-yl,1-(4-chlorophenoxyethyl)piperidin-4-yl, 1-phenylpiperidin-4-yl,1-benzylpyrrolidin-3-yl, trans-phenethenyl, trans-4-fluorophenethenyl,phenyl, 4-fluorophenyl, 4-dimethylarinophenyl, 2,4,6-trimethylphenyl,4-(diethylaminomethyl)phenyl, 4-(piperidin-1-ylmethyl)phenyl,4-(pyrolidin-1-ylmethyl)phenyl, 4-(thiomorpholin-4-ylmethyl)phenyl,2,3-dihydrobenzofuran-5-yl, 3-(4-(2-phenylethyl)piperazin-1-yl)propyl,3-(4-cyclohexyhnethylpiperazin-1-yl)propyl,3-(4-cyclopentylpiperazin-1-yl)propyl,3-(4-iso-propylpiperazin-1-yl)propyl, 3-(4-phenylpiperazin-1-yl)propyl,4-(4-ethylpiperazin-1-yl)butyl, 3-(piperidin-1-ylmethyl)phenyl,4-(diethylaminomethyl)phenyl, 4-(4-ethylpiperazin-1-ylmethyl)phenyl,benzothien-2-yl, 4-methoxybenzyl or benzyloxymethyl.

When R² is unsubstituted or substituted aryl, examples include phenyl,biphenyl and naphthalenyl.

When R² is substituted aryl, suitable substituents include up to fivegroups independently selected from the list consisting of benzyloxy,halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₃alkylenedioxy, C₁₋₆alkylcarbonylamnino,perhaloC₁₋₆alkyl, nitro, perhaloC₁₋₆alkoxy, formyl, C₁₋₆alkoxycarbonyl,carboxy, cyano, morpholinylalkyl, hydroxy, di-(C₁₋₆alkyl)aminoalkoxy,morpholinylalkoxy, or di-(C₁₋₆alkyl)amino.

When R² is unsubstituted heteroaryl, examples include thienyl, furanyl,indolyl, pyridin-2-yl, pyridin-3-yl, quinolin-3-yl, benzodioxolanyl,pyrimidinyl, pyrazinyl and benzthiophenyl.

When R² is substituted heteroaryl, suitable substituents include up tofive groups independently selected from the list consisting ofC₁₋₆alkoxycarbonylamino, cyanoC₁₋₆alkyl, amino, pyrrolyl, ureido,phenyl, hydroxyC₁₋₆alkylamino, formylaminoC₁₋₆alkylamino, piperidinyl,aminocarbonyl, C₁₋₆alkoxycarbonylC₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkoxy, halo, and C₁₋₆alkyl.

When Y is CH or N, suitably R² is phenyl, pyridin-3-yl, pyridin-4-yl,2-thienyl, 2-benzyloxyphenyl, 2-chlorophenyl, 2-fluorophenyl,2-methylphenyl, 2-methoxypyrid-3-yl, 2-methoxyphenyl,3,4-methylenedioxyphenyl, 3,5-dichlorophenyl, 3-acetamidophenyl,3-trifluoromethylphenyl, 3-chlorophenyl, 3-fluorophenyl, furan-3-yl,3-methoxyphenyl, 3-nitrophenyl, 3-thienyl, 4-trifluoromethylphenyl,4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl,4-trifluoromethoxyphenyl, indol-5-yl, 4-methoxypyridin-3-yl,2-chloro-3-fluorophenyl, 2,3-difluorophenyl, 2,3,6-trifluorophenyl,3-methylphenyl, pyridin-2-yl, quinolin-3-yl, 2-formylphenyl,3-formylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 3-cyanophenyl,2-[(morpholin-4-yl)methyl]phenyl, 3-[(morpholin-4-yl)methyl]phenyl,4-[(morpholinfyl)methyl]phenyl, 2-[2-(morpholin-4-yl)ethyl]phenyl,3-[2-(morpholin-4-yl)ethyl]phenyl, 4-[2-(morpholin-4-yl)ethyl]phenyl,3-hydoxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl,2-(dimethylanminoethoxy)phenyl, 3-(dimethylaminoethoxy)phenyl,4-(dimethylaminoethoxy)phenyl, 2-(3-dimethylaminopropoxy)phenyl,3-(3-dimethylanminopropoxy)phenyl, 4-(3-dimethylaminopropoxy)phenyl,2-[(morpholin-4-yl)ethoxy]phenyl, 3-[(morpholin-4-yl)ethoxy]phenyl,4-[(morpholin-4-yl)ethoxy]phenyl, 2-[3-(morpholin-4-yl)propoxy]phenyl,3-[3-(morpholin-4-yl)propoxy]phenyl,4-[3-(morpholin-4-yl)propoxy]phenyl, 1,3-benzodioxolan-5-yl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, 3-chloro-4-fluorophenyl, 2,5-dichlorophenyl,2,4-dichlorophenyl., 2,6-dichlorophenyl, 2,3,5-trifluorophenyl,2,3,4-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl,3,4,5-trifluorophenyl, 3-dimethylaminophenyl, 2-chloropyridin-3-yl,6-chloropyridin-3-yl, 2-chloro-5-methylpyridin-3-yl,2-chloro-4,5-dimethylpyridin-3-yl, 2,5-dimethylpyridin-3-yl,2-(t-butoxycarbonylamino)pyridin-3-yl, 2-(cyanomethyl)pyridin-3-yl,6-aminopyridin-3-yl, 6-(pyrrol-1-yl)pyridin-3-yl, 6-ureidopyridin-3-yl,5-phenylpyridin-3-yl, 2-amino-5-methylpyridin-3-yl,2-methyl-6-aminopyridin-3-yl, 5-methyl-6-aminopyridin-3-yl,5-methyl-6-(3-hydroxypropylamino)pyridin-3-yl,5-methyl-6-[3-(formylamino)propylamino]pyridin-3-yl,5-(piperidin-1-yl)pyridin-3-yl, 5-aminocarbonylpyridin-3-yl,5-(methoxycarbonylmethylcarbonyl)pyridin-3-yl,5-ethoxycarbonylpyridin-3-yl, 5-methoxypyridin-3-yl,4-methylpyridin-3-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrazin-2-yl,naphthalen-1-yl, furan-2-yl, biphenyl-4-yl, or benzo[b]thiophen-3-yl.

When Y is CH preferably R² is phenyl, pyridin-3-yl, 2-thienyl,2-benzyloxyphenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl,2-methoxypyrid-3-yl, 2-methoxyphenyl, 3,4-methylenedioxyphenyl,3,5-dichlorophenyl, 3-acetamidophenyl, 3-trifluoromethylphenyl,3-chlorophenyl, 3-fluorophenyl, furan-3-yl, 3-methoxyphenyl,3-nitrophenyl, 3-thienyl, 4-trifluoromethylphenyl, 4-chlorophenyl,4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl,4-trifluoromethoxyphenyl, indol-5-yl 4-methoxypyridin-3-yl,2-formylphenyl, 3-formylphenyl, 3-methoxycarbonylphenyl,3-carboxyphenyl, 3-cyanophenyl, 2-[(morpholin-4-yl)methyl]phenyl,3-[(morpholin-4-yl)methyl]phenyl, 4-[(morpholin-4-yl)methyl]phenyl,2-[2-(morpholin-4-yl)ethyl]phenyl, 3-[2-(morpholin-4-yl)ethyl]phenyl,4-[2-(morpholin-4-yl)ethyl]phenyl, 3-hydoxyphenyl, 4-hydroxyphenyl,3-methoxyphenyl, 2-(dimethylaminoethoxy)phenyl,3-(dimethylaminoethoxy)phenyl, 4-(dimethylaminoethoxy)phenyl,2-(3-dimethylaminopropoxy)phenyl, 3-(3-dimethylaminopropoxy)phenyl,4-(3-dimethylaminopropoxy)phenyl, 2-[(morpholin-4-yl)ethoxy]phenyl,3-[(morpholin-4-yl)ethoxy]phenyl, 4-[(morpholin-4-yl)ethoxy]phenyl,2-[3-(morpholin-4-yl)propoxy]phenyl,3-[3-(morpholin-4-yl)propoxy]phenyl,4-[3-(morpholin-4-yl)propoxy]phenyl, 1,3-benzodioxolan-5-yl,2,3-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 2-fluoro-4-chlorophenyl,3-fluoro-4-chlorophenyl, 2-chlorofluorophenyl, 3-chloro-4-fluorophenyl,2,5-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl,2,3,6-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,4-trifluorophenyl,2,4,6-tifluorophenyl, 2,4,5-trifluorophenyl, 3,4,5-trifluorophenyl,3-dimethylaminophenyl, pyridin-2-yl, pyridin-4-yl, 2-chloropyridin-3-yl,6-chloropyridin-3-yl, 2-chloro-5-methylpyridin-3-yl,2-chloro-4,5-dimethylpyridin-3-yl, 2,5-dimethylpyridin-3-yl,2-(t-butoxycarbonylamino)pyridin-3-yl, 2-(cyanomethyl)pyridin-3-yl,6-aminopyridin-3-yl, 6-(pyrrol-1-yl)pyridin-3-yl, 6-ureidopyridin-3-yl,5-phenylpyridin-3-yl, 2-amino-5-methylpyridin-3-yl,2-methyl-6-aminopyridin-3-yl, 5-methyl-6-aminopyridin-3-yl,5-methyl-6-(3-hydroxypropylamino)pyridin-3-yl,5-methyl-6-[3-(formylamino)propylamino]pyridin-3-yl,5-(piperidin-1-yl)pyridin-3-yl, 5-aminocarbonylpyridin-3-yl,5-(methoxycarbonylmethylcarbonyl)pyridin-3-yl,5-ethoxycarbonylpyridin-3-yl, 5-methoxypyridin-3-yl,4-methylpyridin-3-yl, quinolin-3-yl, pyrimidin-5-yl, pyrimidin-2-yl,pyrazin-2-yl, naphthalen-1-yl, furan-2-yl, biphenyl-4-yl,benzo[b]thiophen-3-yl,

When Y is N, preferably R² is phenyl, 2-chlorophenyl,2-chloro-3-fluorophenyl, 2,3-difluorophenyl, 2,3,6-trifluorophenyl,3-methylphenyl, pyridin-2-yl, pyridin-3-yl or quinolin-3-yl.

Further preferred compounds of formula (I) include those wherein,

-   R¹ is methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, cyclobutyl,    cyclopentyl, pyridin-3-ylmethyl, 3-(morpholin-4-yl)propyl,    3-(meso-3,5-dimethylmorpholin-4-yl)propyl, benzyl,    3-(N,N-dimethylanino)propyl, 3-(pyrrolidin-1-yl)propyl,    piperidin-4-yl, 1-methylpiperidin-4-yl, 3-(piperidin-1-yl)propyl,    3-(4-ethylpiperazin-1-yl)propyl, 4-(diethylaminomethyl)phenyl,    3-(N,N-diethylamino)propyl,    3-(1,1-dioxo-1-thiomorpholin-4-yl)propyl,    1-(methoxyethyl)piperidin-4-yl, methoxymethyl, methoxyethyl,    phenoxymethyl, benzyloxymethyl, 1-ethylpiperidin-4-yl,    methoxyethoxymethyl, 1-benzylpiperidin-4-yl,    3-(4-methanesulfonylpiperazin-1-yl)propyl,    N-methoxyethyl(N-methyl)aminopropyl, 4-(piperidin-1-yl)butyl,    2,2,2-trifluoroethoxymethyl,    (1-(4-fluorobenzyl)piperidin-4-yl)methyl, 1-benzylpyrrolidin-3-yl,    (1-ethylpiperidin-4-yl)methyl, 4-dimethylaminophenyl,    4-fluorophenethyl, 4-(piperidin-1-ylmethyl)phenyl,    (1-methylpiperidin-4-yl)methyl, 4-(dimethylaminomethyl)benzyl,    (6-methylpyridin-3-yl)ethyl, 1-(4-fluorobenzyl)piperidin-4-yl,    4-(4-ethylpiperazin-1-yl)butyl,    4-(4-ethylpiperazin-1-ylmethyl)phenyl,    3-(4-cyclopentylpiperazin-1-yl)propyl,    3-(4-cyclohexylmethylpiperazin-1-yl)propyl and 4-methoxybenzyl; and-   R² is pyridin-2-yl, pyridin-3-yl, phenyl, 3-fluorophenyl, 3-thienyl,    4-methoxypyridin-3-yl, 2,3-difluorophenyl, 2,5-difluorophenyl,    3,5-difluorophenyl, 2,6-difluorophenyl, furan-2-yl,    2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl,    pyrimidin-2-yl, quinolin-3-yl, 3-hydroxyphenyl,    4-methylpyridin-3-yl, 2-chloro-5-methylpyridin-3-yl,    6-aminopyridin-3-yl, 6-ureidopyridin-3-yl, 2-chloropyridin-3-yl,    6-chloropyridin-3-yl, 5-(piperidin-1-yl)pyridin-3-yl,    5-methyl-6-aminopyridin-3-yl,    5-(methoxycarbonylmethylcarbonyl)pyridin-3-yl,    5-methoxypyridin-3-yl, 5-aminocarbonylpyridin-3-yl,    5-phenylpyridin-3-yl, 3-formylphenyl, 3-methylphenyl, 2-chlorophenyl    and 2-chloro-3-fluorophenyl.

Particularly preferred compounds of formula (I) where Y is CH includethose wherein,

-   R¹ is ethyl, n-propyl, iso-propyl, cyclopropyl, cyclobutyl,    cyclopentyl, pyridin-3-ylmethyl, 3-(morpholin-4-yl)propyl and    3-(meso-3,5-dimethylmorpholin-4-yl)propyl; and-   R² is pyridin-2-yl, pyridin-3-yl, phenyl, 3-fluorophenyl, 3-thienyl,    4-methoxypyridin-3-yl, 2,3-difluorophenyl, 2,5-difluorophenyl,    3,5-difluorophenyl, 2,6-difluorophenyl, furan-2-yl,    2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl,    pyrimidin-2-yl, quinolin-3-yl, 3-hydroxyphenyl,    4-methylpyridin-3-yl, 2-chloro-5-methylpyridin-3-yl,    6-aminopyridin-3-yl, 6-ureidopyridin-3-yl, 2-chloropyridin-3-yl,    6-chloropyridin-3-yl, 5-(piperidin-1-yl)pyridin-3-yl,    5-methyl-6-aminopyridin-3-yl,    5-(methoxycarbonylmethylcarbonyl)pyridin-3-yl,    5-methoxypyridin-3-yl, 5-aminocarbonylpyridin-3-yl,    5-phenylpyridin-3-yl and 3-formylphenyl.

Particularly preferred compounds of formula (I) where Y is N includethose wherein,

-   R¹ is methyl, n-propyl, iso-propyl, cyclopropyl, cyclopentyl,    benzyl, 3-(N,N-dimethylamino)propyl, 3-(morpholin-4-yl)propyl,    3-(pyrrolidin-1-yl)propyl, piperidin-4-yl, 1-methylpiperidin-4-yl,    3-(piperidin-1-yl)propyl, 3-(4-ethylpiperazin-1-yl)propyl,    4-(diethylaminomethyl)phenyl, 3-(N,N-diethylamino)propyl,    3-(1,1-dioxo-1-thiomorpholin-4-yl)propyl,    1-(methoxyethyl)piperidin-4-yl, methoxymethyl, methoxyethyl,    phenoxymethyl, benzyloxymethyl, 1-ethylpiperidin-4-yl,    methoxyethoxymethyl, 1-benzylpiperidin-4-yl,    3-(4-methanesulfonylpiperazin-1-yl)propyl,    N-methoxyethyl(N-methyl)aminopropyl, 4-(piperidin-1-yl)butyl,    2,2,2-trifluoroethoxymethyl,    (1-(4-fluorobenzyl)piperidin-4-yl)methyl, 1-benzylpyrrolidin-3-yl,    (1-ethylpiperidin-4-yl)methyl, 4-dimethylaminophenyl,    4-fluorophenethyl, 4-(piperidin-1-ylmethyl)phenyl,    (1-methylpiperidin-4-yl)methyl, 4-(dimethylaminomethyl)benzyl,    (6-methylpyridin-3-yl)ethyl, 1-(4-fluorobenzyl)piperidin-4-yl,    4-(4ethylpiperazin-1-yl)butyl,    4-(4-ethylpiperazin-1-ylmethyl)phenyl,    3-(4-cyclopentylpiperazin-1-yl)propyl,    3-(4-cyclohexylmethylpiperazin-1-yl)propyl and 4-methoxybenzyl; and-   R² is phenyl, 3-methylphenyl, 2,3-difluorophenyl, 2-chlorophenyl,    2-chloro-3-fluorophenyl, 2,3,6-trifluorophenyl, pyridin-3-yl and    quinolin-3-yl.

Certain of the compounds of formula (I) may contain chiral atoms and/ormultiple bonds, and hence may exist in one or more stereoisomeric forms.The present invention encompasses all of the isomeric forms of thecompounds of formula (I) whether as individual isomers or as mixtures ofisomers, including-geometric isomers and racemic modifications.

Alkyl groups referred to herein, including those forming part of othergroups, include straight or branched chain alkyl groups containg up totwelve, suitably up to six carbon atoms. These alkyl groups may beoptionally substituted with up to five, suitably up to three, groupsselected from the list consisting of aryl, heterocyclyl, alkylthio,alkenylthio, alkynylthio, arylthio, heterocyclylthio, alkoxy,arylalkoxy, arylalkylthio, ammo, mono- or di-alkylamino, cycloalkyl,cycloalkenyl, carboxy and esters thereof, phosphonic acid and estersthereof, mono- or dialkylaminosulphonyl, aminosulphonyl, cyano,alkylcarbonylamino, arylcarbonylamino, arylaminocarbonyl,arylalkylaminocarbonyl arylalkylcarbonylamino, thiazolidinedionyl,piperazinylcarbonyl wherein the piperazine may be unsubstituted orsubstituted, morpholinylcarbonyl, piperidinylcarbonyl,hydroxyalkylaminocarbonyl, dialylaminocarbonyl, aminocarbonyl,dialkylaminoalkylaminocarbonyl, alkoxycarbonylamino,alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino,alkoxycarbonylalkylcarbonylamino, alkylaminocarbonyl, aminosulphonyl,arylsulphonylamino, alkylsulphonylamino, hydroxy,morpholinylalkylaminocarbonyl, hydroxyaminocarbonyl, aryloxy,heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylalkylthio andhalogen.

Alkenyl and alkynyl groups referred to herein include straight andbranched chain groups containing from two to twelve, suitably from twoto six, carbon atoms. These alkenyl and alkynyl groups may be optionallysubstituted with up to five, suitably up to three, groups includingthose substituents described hereinbefore for the alkyl groups.

Cycloalkyl and cycloalkenyl groups referred to herein include groupshaving between three and eight ring carbon atoms. These cycloalkyl andcycloalkenyl groups may be optionally substituted with up to five,suitably up to three, groups including those substituents hereinbeforedescribed for the alkyl groups.

As used herein, the term “aryl” includes phenyl, naphthenyl, andbiphenyl groups, especially phenyl. Suitable optional substituents forany aryl group include up to five substituents selected from the listconsisting of perhaloalkyl, arylaminocarbonyl, aralcyaminocarbonyl,hydroxyalkylaminocarbonyl, arylamino, aminosulphonyl,alkylsulphonylamino, mono- and di-alcylamino, mono- anddi-alkylaminocarbonyl, arylaminocarbonylalkyl, arylcarbonyl, aralkoxy,heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylalkylthio,arylcarbonylamino, alkoxyalkylaminocarbonyl, arallylcarbonylamino,aralklylcarbonylaminoalkyl, aminocarbonyl,morpholinylalkylaminocarbonylalkyl, arylaminosulphonyl,arylcarbonylaminoalkyl, arylsulphonylamino, aminocarbonylalkyl,hydroxyaminocarbonylalkyl, aryl, alkylcarbonylamino, alkylenedioxy,perhaloalkoxy, thiazolidinedionylalkyl, carboxyalkoxy,(methylpiperazinyl)carbonylalkyl, morpholinyl, morpholinylcarbonylalkyl,piperidinylcarbonylalkyl, hydroxyalkylamninocarbonylalkyl, mono- anddi-alkylaminocarbonylalkyl, alkoxyalkylaminosulphonyl, alkoxyamino,perhaloalkylcarbonylamino, alkylaminosulphonylalkyl, mono- anddi-alkylaminoalkylaminocarbonylalkyl, carboxyalkoxy,alkoxycarbonylaminoalkyl, aminocarbonylalkenyl,alkoxyalkylcarbonylamino, alkylcarbonylaminoalkylcarbonylamino,alkylcarbonylaminoalkyl, hydroxyalkylcarbonylamino,alkoxycarbonylalkylcarbonylamino, carboxyalkylcarbonylamino,alkoxyalkylcarbonylaminoalkyl,alkylcarbonylaminoaIkylcarbonylaminoalkyl,hydroxyalkylcarbonylaminoalkyl, carboxyalkenyl,aminocarbonylalkylcarbonylamino, alkylaminocarbonylalkoxy,alkylaminosulphonylalkyl, aminocarbonylalkyl, oxazolyl,pyridinylalkylcarbonylamino, methyloxazolyl, alkylthio,alkylaminocarbonylalkyl, halo, alkyl, alkenyl, substituted alkenyl,arylalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkyloxy, hydroxy,hydroxyalkyl, nitro, amino, cyano, cyanoalkyl , mono- anddi-N-alkylamino, acyl, acylamino, N-alkylacylamino, acyloxy, carboxy,carboxyalkyl, carboxyalkylcarbonyl, carboxyalkenyl, ketoalkylester,carbamoyl, carbamoylalkyl, mono- and di-N-alkylcarbamoyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxy, arylthio, aralkyloxy,aryloxycarbonyl, ureido, guanidino, morpholino, adamantyl, oxazolyl,aminosulphonyl, alkylaminosulphonyl, alkylthio, haloalkylthio,alkylsulphinyl, alkylsulphonyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, alkoxycarbonyl, trityl, substituted trityl, mono- orbis-alkylphosphonate or mono- or bis-alkylphosphonateC₁₋₆alkyl or anytwo adjacent substituents on the phenyl ring together with the carbonatoms to which they are attached form a carbocyclic ring or aheterocyclic ring.

As used herein the terms “heterocyclyl” and “heterocyclic” suitablyinclude, unless otherwise defined, aromatic and non-aromatic, single andfused, rings suitably containing up to four heteroatoms in each ring,each of which is selected from oxygen, nitrogen and sulphur. Each ringsuitably has from 4 to 7, preferably 5 or 6, ring atoms. Theseheterocyclyl and heterocyclic rings may be unsubstituted or substitutedby up to five substituents. A fused heterocyclic ring system may includecarbocyclic rings and need include only one heterocyclic ring. Examplesinclude furyl, piperazinyl, thienyl, piperidinyl, pyridazinyl,morpholinyl, pyridinyl, indolinyl, quinolinyl, indolyl, benzoxazolyl,benzothiazolyl, benzothiazolinonyl, benzoxazolinonyl, and quarternisedpyridinyl and salts thereof. Suitable substituents for any heterocyclylor heterocyclic group are selected from cyano, carboxyalkoxy,morpholinyl, hydroxyalkylaminocarbonyl, alkoxyalkylaminosulphonyl,alkylaminosulphonyl, arylcarbonylamino, aralkylcarbonylamino,aralkenylcarbonylamino, perhalocarbonylamino, perhaloalkyl,aminocarbonyl, nitro, aminocarbonylalkenyl, alkoxyalkylcarbonylamino,alkylcarbonylamninoalkylcarbonylamino, hydroxyalkylcarbonylamino,carboxyalkenyl, aminocarbonylalkylcarbonylamino,alkylaminocarbonylalkoxy, aryl, arylcarbonyl, alkylenedioxy, aryloxy,aralkyloxy, perhaloalkylthio, alkylcarbonyl, alkoxycarbonylalkylthio,carboxyalkylthio, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, carboxyalkyl,alkoxycarbonyl, halogen, alkyl, arylalkyl, alkoxy, alkoxyalkyl,haloalkyl, hydroxy, amino, mono- and di-N-alkylamino, acylamino, carboxyand salts and esters thereof, carbamoyl, mono- anddi-N-alkylaminocarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl, aryl, oxygroups, ureido, guanidino, sulphonylamino, aminosulphonyl, alkylthio,alkylsulphinyl, alkylsulphonyl, hydroxy, alkylcarbonylamino,heterocyclyl and heterocyclylalkyl.

As used herein the term “heteroaryl” suitably includes, unless otherwisedefined, aromatic single and fused rings suitably containing up to fourheteroatoms in each ring, each of which is selected from oxygen,nitrogen and sulphur. Each ring suitably has from 4 to 7, preferably 5or 6, ring atoms. These heteroaryl rings may be unsubstituted orsubstituted by up to five substituents. A fused heteroaryl ring systemmay include carbocyclic rings and need include only one heteroaryl ring.Examples include furyl, thienyl, pyridazinyl, pyridyl, quinolinyl,indolyl, benzoxazolyl and benzothiazolyl. Suitable substituents for anyheteroaryl group are selected from cyano, carboxyalkoxy, morpholinyl,hydroxyalkylaminocarbonyl, alkoxyalkylaminosulphonyl,alkylaminosulphonyl, arylcarbonylamino, aralkylcarbonylamino,aralkenylcarbonylamino, perhalocarbonylamino, perhaloalkyl,aminocarbonyl, nitro, aminocarbonylalkenyl, alkoxyalkylcarbonylamino,alkylcarbonylaminoalkylcarbonylamino, hydroxyalkylcarbonylamino,carboxyalkenyl, aminocarbonylalkylcarbonylamino,alkylaminocarbonylalkoxy, aryl, arylcarbonyl, alkylenedioxy, aryloxy,aralkyloxy, perhaloalkylthio, alkylcarbonyl, alkoxycarbonylallylthio,carboxyalkylthio, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, carboxyalkyl,alkoxycarbonyl, halogen, alkyl, arylalkyl, alkoxy, allcoxyalkyl,haloalkyl, hydroxy, amino, mono- and di-N-alkylamino, acylarmino,carboxy and salts and esters thereof, carbamoyl, mono- anddi-N-alkylaminocarbonyl, aryloxycarbonyl, alkoxycarbonylalkcyl, aryl,oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl,alkylthio, alkylsulphinyl, alkylsulphonyl, hydroxy, alkylcarbonylamino,heterocyclyl and heterocyclylalkyl.

As used herein the terms “halogen” or “halo” include iodo, bromo, chloroor fluoro, especially chloro or fluoro.

Suitable derivatives of the compounds of the invention arepharmaceutically acceptable derivatives.

Suitable derivatives of the compounds of the invention include salts andsolvates.

Suitable pharmaceutically acceptable derivatives includepharmaceutically acceptable salts and pharmaceutically acceptablesolvates.

Suitable pharmaceutically acceptable salts include metal salts, such asfor example aluminium, alkali metal salts such as lithium, sodium orpotassium, alkaline earth metal salts such as calcium or magnesium andammonium or substituted ammonium salts, for example those with loweralkylamines such as triethylamine, hydroxy alkylamines such as2-hydroxyethyl amine, bis-(2-hydroxyethyl)amine ortri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

Suitable pharmaceutically acceptable salts also includespharmaceutically acceptable acid addition salts, such as those providedby pharmaceutically acceptable inorganic acids or organic acids.

Suitable pharmaceutically acceptable acid addition salts provided bypharmaceutically acceptable inorganic acids includes the sulphate,nitrate, phosphate, borate, hydrochloride and hydrobromide andhydroiodide.

Suitable pharmaceutically acceptable acid addition salts provided bypharmaceutically acceptable organic acids includes the acetate,tartrate, maleate, fumarate, malonate, citrate, succinate, lactate,oxalate, benzoate, ascorbate, methanesulphonate, α-keto glutarate andα-glycerophosphate.

Suitable pharmaceutically acceptable solvates include hydrates.

For the avoidance of doubt when used herein the term “diabetes” includesdiabetes mellitus, especially Type 2 diabetes, and conditions associatedwith diabetes mellitus.

The term “conditions associated with diabetes” includes those conditionsassociated with the pre-diabetic state, conditions associated withdiabetes mellitus itself and complications associated with diabetesmellitus.

The term “conditions associated with the pre-diabetic state” includesconditions such as insulin resistance, impaired glucose tolerance andhyperinsulinaemia.

The term “conditions associated with diabetes mellitus itself” includehyperglycaemia, insulin resistance and obesity. Further conditionsassociated with diabetes mellitus itself include hypertension andcardiovascular disease, especially atherosclerosis and conditionsassociated with insulin resistance. Conditions associated with insulinresistance include polycystic ovarian syndrome and steroid inducedinsulin resistance.

The term “complications associated with diabetes mellitus” includesrenal disease, especially renal disease associated with Type IIdiabetes, neuropathy and retinopathy. Renal diseases associated withType II diabetes include nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclercsis and endstage renal disease.

A further aspect of the invention provides a process for the preparationof a compound of formula (I), or a derivative thereof, which processcomprises reaction of a compound of formula (II),

wherein;

Y and R² are as defined in formula (I), with a compound of formula (III)

wherein;

R¹ is as defined in formula (I) and X is a leaving group, andthereafter, if required, carrying out one or more of the followingoptional steps:

-   (i) converting a compound of formula (I) to a further compound of    formula (I);-   (ii) removing any necessary protecting group;-   (iii) preparing an appropriate derivative of the compound so formed.

An example of a suitable leaving group, X, is chloro.

The reaction between the compounds of formulae (II) and (III) is carriedout in a suitable solvent under conventional amidation conditions at asuitable temperature providing a suitable rate of formation of therequired product, generally at an elevated temperature, over a suitablereaction time. Suitable solvents include pyridine. Suitable reactiontemperatures include those in the range of 60° C. to 220° C. and, asappropriate, the reflux temperature of the solvent Suitable reactiontimes are those in the range 12–72 hours. If the compound of formula(II) is a weak nucleophile, then the reaction may be assisted by, forexample, using temperatures at the upper end of this range, or by usinga hindered base catalyst such as dimethylaminopyridine (DMAP). Ahindered base is a base which does not act as a competing nucleophile.The reaction products are isolated using conventional methods.Alternatively, the reaction may be assisted by the use of an excess ofthe compound of formula (III). It will be appreciated that where R¹and/or R² are non-basic, a suitable method of isolation involves coolingthe reaction mixture, acidifying the resulting residue using a suitableacid and isolating the product by filtration. A suitable acid is adilute mineral acid, for example dilute hydrochloric acid. Conventionalmethods of heating and cooling may be employed, for example electricheating mantles and ice/salt baths respectively. The reaction productsare purified by conventional methods, such as crystallisation,chromatography and trituration. Crystalline product may be obtained bystandard methods.

In the reaction of a compound of formula (I) with a compound of formula(In), a compound of formula (IV) may be formed

wherein;

R¹ and R² are as hereinbefore defined.

A compound of formula (IV) may be converted into a compound of formula(I) either in situ or in a separate step, by reaction with a suitablenucleophile, such as piperidine.

Compounds of formula (IV) are considered to be novel and accordinglyform a further aspect of the invention.

In a preferred aspect, the compound of formula (III) is added to asolution of the compound of formula (II) in pyridine. The reactionmixture is stirred at reflux for 16 hours and allowed to cool. Themixture is acidified to pH 1 with 5N HCl and the solid isolated byfiltration. Where Y is CH, the crude product is purified by conventionalmethods, for example chromatography, trituration or crystallisation fromone or more suitable solvents such as DMF/methanol. Where Y is N one ofthe following steps is employed:

-   -   a) The mixture is acidified to pH 1 with 5N HCl and the solid        isolated by filtration; or    -   b) The mixture is concentrated in vacuo; or    -   c) The mixture is concentrated in vacuo and the residue        azeotroped with water and then with ethanol; or    -   d) The mixture is concentrated in vacuo and the residue        azeotroped with ethanol and then dissolved in methanol and        absorbed onto a column pre-packed with a suitable acidic        ion-exchange resin. The column is washed with methanol and the        product subsequently eluted with 0.5N ammonia in methanol        solution; and

The resulting crude product is purified by chromatography, for example,silica gel chromatography or reverse-phased preparative HPLC. It will beappreciated that the purification of a compound of formula (I) mayrequire more than one chromatography step, and may additionally requiresubsequent purification with a suitable acidic ion-exchange resin. Itwill be appreciated that suitable acidic ion-exchange resins includethose commercially available, for example, SCX resin.

In a further preferred aspect, the compound of formula (III) is added toa solution of a compound of formula (II) in pyridine. The reactionmixture is stirred at reflux for 72 hours and allowed to cool, thenevaporated in vacuo. Piperidine is added and the mixture stirred for afurther 16 hours at ambient temperature. The solvents are removed undervacuum, and the residue azeotroped with ethanol. The crude product ispurified by silica gel chromatography.

Compounds of formula (II) are believed to be novel and accordingly forma further aspect of the invention.

A still further aspect of the invention provides a process for thepreparation of a compound of formula (I) where Y is CH, or a derivativethereof, which process comprises reaction of a compound of formula (V),

wherein;

R¹ is as defined in formula (I), with a compound of formula (VI)R²—B(OR³)₂  (VI)wherein;

R² is as defined in formula (I) and R³ is hydrogen or C₁₋₆alkyl andthereafter, if required, carrying out one or more of the followingoptional steps:

-   (i) converting a compound of formula (I) to a further compound of    formula (I);-   (ii) removing any necessary protecting group;-   (iii) preparing an appropriate derivative of the compound so formed.

Suitably, R³ is hydrogen.

The reaction between the compounds of formulae (V) and (VI) is carriedout in a suitable degassed solvent in the presence of a suitablecatalyst and a suitable base at a suitable temperature providing asuitable rate of formation of the required product, generally anelevated temperature, over a suitable reaction time. Suitable solventsinclude DMF/ethanol. Suitable catalysts includetetrakis(triphenylphosphine)palladium(0). Suitable bases include aqueoussodium bicarbonate. Suitable reaction temperatures include those in therange of 60° C. to 220° C. and, as appropriate, the reflux temperatureof the solvent. Suitable reaction times are those in the range 8–24hours. The reaction products are isolated using conventional methods.Typically, the reaction mixture is cooled, water added, and the productsisolated by filtration. Conventional methods of heating and cooling maybe employed, for example electric heating mantles and ice/salt bathsrespectively. The reaction products are purified by conventionalmethods, such as crystallisation, chromatography and trituration.Crystalline product may be obtained by standard methods.

In a preferred aspect, tetralis(triphenylphosphine)palladium(0) is addedto a degassed solution of the compound of formula (V), the compound offormula (VI), and aqueous sodium bicarbonate in DMF/ethanol. Thereaction mixture is stirred at reflux for 12 hours, cooled, and wateradded. The crude product is isolated by filtration and purified bycolumn chromatography.

Compounds of formula (V) are believed to be novel and accordingly form afurther aspect of the invention.

A still further aspect of the invention provides a process for thepreparation of a compound of formula (I), or a derivative thereof, whichprocess comprises reaction of a compound of formula (VII),

wherein;

R¹ is as defined in formula (I) and Z is the moiety (R⁴O)₂B—, wherein R⁴is hydrogen or C₁₋₆alkyl or Z is the moiety (VIII),

wherein;

R⁵ is C₁₋₆alkyl with a compound of formula (IX),R²—X′  (IX)wherein;

R² is as defined in formula (I) and X′ is a leaving group, for examplehalogen, and thereafter, if required, carrying out one or more of thefollowing optional steps:

-   (i) converting a compound of formula (I) to a further compound of    formula (I);-   (ii) removing any necessary protecting group;-   (iii) preparing an appropriate derivative of the compound so formed.

Suitably, X′ is bromo.

Suitably, Z is a moiety of formula (VIII).

Suitably, R⁵ is methyl.

The reaction between the compounds of formulae (VII) and (IX) is carriedout in a suitable degassed solvent in the presence of a suitablecatalyst and a suitable base at a suitable temperature providing asuitable rate of formation of the required product, generally anelevated temperature, over a suitable reaction time. Suitable solventsinclude a mixture of DMF/ethanol/water. Suitable catalysts includetetrakis(triphenylphosphine)palladium(0). Suitable bases includepotassium acetate. Suitable reaction temperatures include those in therange of 60° C. to 220° C. and, as appropriate, the reflux temperatureof the solvent. Suitable reaction times are those in the range 8–24hours. Typically, the reaction mixture is cooled, and the productisolated by conventional means. Conventional methods of heating andcooling may be employed, for example electric heating mantles andice/salt baths respectively. The reaction products are purified byconventional methods, such as crystallisation, chromatography andtrituration. Crystalline product may be obtained by standard methods.

In a preferred aspect, tetrakis(triphenylphosphine)palladium(0) is addedto a stirred and degassed solution of the compound of formula (VII), thecompound of formula (IX), and aqueous potassium acetate inDMF/ethanol/water. The reaction mixture is stirred at reflux for 18hours, cooled, ethyl acetate added, and the mixture washed with aqueoussodium bicarbonate and brine. The organic layer is isolated, dried withmagnesium sulphate, and evaporated. The crude product is purified bycolumn chromatography.

Compounds of formula (VII) are believed to be novel and accordingly forma further aspect of the invention.

The above-mentioned conversions of a compound of formula (I) intoanother compound of formula (I) includes any conversion which may beeffected using conventional procedures, but in particular the saidconversions include any combination of:

-   (i) converting one group R¹ into another group R¹;-   (ii) converting one group R² into another group R².

The above-mentioned conversions (i) and (ii) may be carried out usingany appropriate method under conditions determined by the particulargroups chosen.

The above mentioned conversions (i) and (ii) may as appropriate becarried out on any of the intermediate compounds mentioned herein.

For example, a compound of formula (I) wherein R¹ represents1-benzylpiperidin-4-yl may be converted into a compound of formula (I)wherein R¹ represents piperidin-4-yl, by treatment of the compound offormula (I) wherein R¹ represents 1-benzylpiperidin-4-yl with ammoniumformate in refluxing ethanol in the presence of 10% Pd/C.

Suitable conversions of one group R¹ into another group R¹, as inconversion (i), include converting a group R¹ which represents a4-bromobutyl group into a group R¹ which represents (1-pyridinium)butylbromide salt, such conversion may be carried out in situ by reacting acompound of formula (III), wherein R¹ is 4-bromobutyl, with a compoundof formula (II) in the presence of pyridine.

The above-mentioned conversions may as appropriate be carried out on anyof the intermediate compounds mentioned herein.

Suitable protecting groups in any of the above-mentioned reactions arethose used conventionally in the art. The methods of formation andremoval of such protecting groups are those conventional methodsappropriate to the molecule being protected. Thus for example abenzyloxy group may be prepared by treatment of the appropriate compoundwith a benzyl halide, such as benzyl bromide, and thereafter, ifrequired, the benzyl group may be conveniently removed using catalytichydrogenation or a mild ether cleavage reagent such as trimethylsilyliodide or boron tribromide.

Where appropriate individual isomeric forms of the compounds of formula(I) may be prepared as individual isomers using conventional procedures.

The absolute stereochemistry of compounds may be determined usingconventional methods, such as X-ray crystallography.

The derivatives of the compounds of formula (I), including salts and/orsolvates, may be prepared and isolated according to conventionalprocedures.

Compounds of formula (II) may be prepared by reaction of a compound offormula (X),

wherein;

Y and R² are as defined in formula (I), with hydrazine, or a hydratethereof.

The reaction between the compound of formula (X) and hydrazine, or ahydrate thereof, is carried out in a suitable solvent at a suitabletemperature providing a suitable rate of formation of the requiredproduct, generally at an elevated temperature, over a suitable reactiontime. Suitable solvents include pyridine and ethanol. Suitable reactiontemperatures include those in the range of 60° C. to 220° C. and, asappropriate, the reflux temperature of the solvent. Suitable reactiontimes are those in the range 148 hours. The reaction products areisolated using conventional methods. Typically, the reaction mixture iscooled, the product isolated by filtration, and dried. Conventionalmethods of heating and cooling may be employed, for example electricheating mantles and ice/salt baths respectively. The reaction productsmay, if desired, be purified by conventional methods, such ascrystallisation, chromatography and trituration.

In a preferred aspect, hydrazine hydrate is added to a stirred solutionof the compound of formula (X) in pyridine. The reaction mixture isstirred at reflux for 6 hours and cooled. The crude product is isolatedby filtration and dried. The crude product may be used withoutpurification.

Compounds of formula (X) where Y is CH may be prepared by reaction of acompound of formula (XI),

wherein;

R² is as defined in formula (I), with a mixture of phosphorusoxychloride and phosphorus pentachloride.

The reaction between the compound of formula (XI) and a mixture ofphosphorus oxychloride and phosphorus pentachloride is carried out at asuitable temperature providing a suitable rate of formation of therequired product, generally an elevated temperature, over a suitablereaction time. Suitable reaction temperatures include the refluxtemperature of the mixture. Suitable reaction times are those in therange 1–48 hours. The reaction products are isolated using conventionalmethods. Typically, the reaction mixture is cooled, and added cautiouslyto iced water. The solution is then basified with a suitable base suchas sodium carbonate and the product isolated by filtration. The productis then washed and dried. Conventional methods of heating and coolingmay be employed, for example electric heating mantles and ice/salt bathsrespectively. The reaction product may, if desired, be purified byconventional methods, such as crystallisation, chromatography andtrituration.

In a preferred aspect, the compound of formula (XI) is added to asuspension of phosphorus oxychloride and phosphorus pentachloride. Thesuspension is stirred at reflux for 1 hour, cooled, and cautiously addedto iced water. The solution is adjusted to pH 11 with sodium carbonateand the product isolated by filtration, washed with water, and dried.The crude product may be used without purification.

Compounds of formula (XI) are either commercially available or areprepared by analogy with known conventional literature procedures, forexample those disclosed in Recl. Trav. Chim. Pays-Bas, 1974, 93, 233, orin standard reference texts of synthetic methodology such as J. March,Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.

Compounds of formula (X) where Y is N are either commercially availableor are prepared by analogy with known conventional literatureprocedures, for example those disclosed in J. Med Chem 1989, 32, 528, orin standard reference texts of synthetic methodology such as J. March,Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.

Compounds of formula (X) where Y is N may also be prepared by thereaction of a compound of formula (XII),

wherein;

R² is as defined in formula (I), with phosphoryl chloride. The reactionbetween the compound of formula (XII) and phosphoryl chloride, iscarried out optionally in a suitable solvent at a suitable temperatureproviding a suitable rate of formation of the required product,generally an elevated temperature, over a suitable reaction time.Suitable reaction temperatures include those in the range of 60° C. to220° C. and, as appropriate, the reflux temperature of the solvent.Suitable reaction times are those in the range 1–48 hours. The reactionproducts are isolated using conventional methods. Typically, thereaction mixture is cooled and evaporated, and the residue dissolved ina suitable solvent and washed with a suitable aqueous base. The organicsolution is then dried with a suitable drying agent and evaporated.Conventional methods of heating and cooling may be employed, for exampleelectric heating mantles and ice/salt baths respectively. The reactionproducts may, if desired, be purified by conventional methods, such ascrystallisation, chromatography and trituratiom

In a preferred aspect, the compound of formula (XII) is dissolved inphosphoryl chloride and heated at reflux for 3 hours, then cooled andevaporated and the residue dissolved in dichloromethane and washed withsaturated sodium bicarbonate solution. The organic solution is thendried with magnesium sulphate and evaporated. The crude product may beused without purification.

Compounds of formula (XII) may be prepared by reaction of a compound offormula (II),

wherein;

R² is as defined in formula (I), with,

-   1) phosphoryl chloride; followed by,-   2) aqueous ammonia.

The reaction between the compound of formula (XIII) and phosphorylchloride (according to step 1 above), is carried out optionally in asuitable solvent at a suitable temperature providing a suitable rate offormation of the required product, generally an elevated temperature,over a suitable reaction time, optionally in the presence of a suitablecatalyst. Suitable reaction temperatures include those in the range of60° C. to 220° C. and, as appropriate, the reflux temperature of thesolvent. Suitable reaction times are those in the range 1–48 hours. Thereaction products are isolated using conventional methods. Typically,the reaction mixture is cooled and evaporated. Conventional methods ofheating and cooling may be employed, for example electric heatingmantles and ice/salt baths respectively.

The reaction between the product of step (1) above and aqueous ammonia(according to step 2 above), is carried out optionally in a suitablesolvent at a suitable temperature providing a suitable rate of formationof the required product, generally an elevated temperature, over asuitable reaction time. Suitable reaction temperatures include those inthe range of 20° C. to 100° C. and, as appropriate, the refluxtemperature of the solvent. Suitable reaction times are those in therange 1–48 hours. The reaction products are isolated using conventionalmethods. Typically, the reaction mixture is diluted with water andextracted with a suitable solvent. The product is isolated from theorganic solution by drying with a suitable drying agent followed byevaporation. Conventional methods of heating and cooling may beemployed, for example electric heating mantles and ice/salt bathsrespectively. The reaction products may, if desired, be purified byconventional methods, such as crystallisation, chromatography andtrituration.

In a preferred aspect, the compound of formula (XIII) is dissolved inphosphoryl chloride containing 3 drops of dry N,N-dimethylformamide andheated at 80° C. for 4 hours, then cooled and evaporated. The residue isdissolved in dry TBF and added with vigorous stirring to concentratedaqueous ammonia solution. After 1 hour the mixture is diluted withwater, extracted with ethyl acetate and the organic solution washed withbrine, dried over magnesium sulphate and evaporated. The crude productmay be used without purification.

Compounds of formula (XIII) may be prepared by reaction of a compound offormula (XIV),

wherein;

R² is as defined in formula (I), and R⁶ represents a straight orbranched chain C₁₋₆alkyl moiety, with sodium hydroxide.

The reaction between the compound of formula (XIV) and sodium hydroxide,is carried out optionally in a suitable solvent at a suitabletemperature providing a suitable rate of formation of the requiredproduct, generally an elevated temperature, over a suitable reactiontime. Suitable reaction temperatures include those in the range of 20°C. to 100° C. and, as appropriate, the reflux temperature of thesolvent. Suitable reaction times are those in the range 1–48 hours. Thereaction products are isolated using conventional methods. Typically,the reaction mixture is cooled and evaporated, and the residue dilutedwith water and filtered. Acidification of the filtrate affords aprecipitate which is filtered, washed with water and dried. Conventionalmethods of heating and cooling may be employed, for example electricheating mantles and ice/salt baths respectively. The reaction productsmay, if desired, be purified by conventional methods, such ascrystallisation, chromatography and trituration.

In a preferred aspect, the compound of formula (XV) is dissolved inethanol and aqueous sodium hydroxide solution and heated at reflux for 2hours, then cooled and evaporated. The residue is diluted with water,filtered, and the filtrate acidified with 2M HCl to afford a precipitatewhich is filtered, washed with water and dried in vacuo. The crudeproduct may be used without purification.

Compounds of formula (XIV) may be prepared by reaction of a compound offormula (XV),

wherein;

R² is as defined in formula (I), and R⁶ represents a straight orbranched chain C₁₋₆alkyl moiety, with hydrazine, or a hydrate, or thehydrochloride thereof.

The reaction between the compound of formula (XV) and hydrazine, or ahydrate, or the hydrochloride thereof, is carried out optionally in asuitable solvent at a suitable temperature providing a suitable rate offormation of the required product, generally an elevated temperature,over a suitable reaction time. Suitable reaction temperatures includethose in the range of 20° C. to 100° C. and, as appropriate, the refluxtemperature of the solvent. Suitable reaction times are those in therange 24–120 hours. The reaction products are isolated usingconventional methods. Typically, the reaction mixture is cooled andevaporated to dryness. Conventional methods of heating and cooling maybe employed, for example electric heating mantles and ice/salt bathsrespectively. The reaction products may, if desired, be purified byconventional methods, such as crystallisation, chromatography andtrituration.

In a preferred aspect, the compound of formula (XV) is dissolved inethanol containing hydrazine monohydrochloride and heated at reflux for96 hours, then cooled and evaporated to dryness. The crude product maybe used without purification.

Compounds of formula (XV) may be prepared by reaction of a compound offormula (XVI),

wherein;

R² is as defined in formula (I), with a diC₁₋₆alkyl ketomalonate.

The reaction between the compound of formula (XVI) and diC₁₋₆alkylketomalonate is carried out optionally in a suitable solvent, at asuitable temperature providing a suitable rate of formation of therequired product, generally an elevated temperature, over a suitablereaction time. Suitable reaction temperatures include those in the rangeof 60° C. to 200° C. and, as appropriate, the reflux temperature of thesolvent. Suitable reaction times are those in the range 24–96 hours. Thereaction products are isolated using conventional methods. Typically,the reaction mixture is diluted with a suitable solvent and purified bychromatography, for example, silica gel chromatography. Conventionalmethods of heating and cooling may be employed, for example electricheating mantles and ice/salt baths respectively.

In a preferred aspect, the compound of formula (XVI) and diethylketomalonate are heated at 140° C. for 48 hours, then cooled. Thereaction mixture is diluted with toluene and chromatographed on silicagel using 20% v/v ethyl acetate in hexane.

Compounds of formula (V) may be prepared by reaction of the compound offormula (XVII),

with a compound of formula (III).

The reaction between the compounds of formulae (XVII) and (III) iscarried out in a suitable solvent at a suitable temperature providing asuitable rate of formation of the required product, generally at anelevated temperature, over a suitable reaction time. A suitable solventis pyridine. Suitable reaction temperatures include the refluxtemperature of the mixture. Suitable reaction times are those in therange 8–24 hours. The reaction products are isolated using conventionalmethods. Typically, the reaction mixture is concentrated in vacuo andwater added. The product isolated by filtration, washed, and dried.Conventional methods of heating and cooling may be employed, for exampleelectric heating mantles and ice/salt baths respectively. The reactionproduct may, if desired, be purified by conventional methods, such ascrystallisation, chromatography and trituration.

In a preferred aspect, the compound of formula (III) is added to asolution of the compound of formula (XVII) in pyridine. The mixture isstirred at reflux for 16 hours then concentrated in vacuo. Water isadded and the product isolated by filtration and dried. The crudeproduct may be used without purification.

The compound of formula (XVII) is believed to be novel and accordinglyforms a further aspect of the invention.

The compound of formula (XVII) may be prepared by reaction of thecompound of formula (XVIII),

with hydrazine, or a hydrate thereof.

The reaction between the compound of formula (XVIII) and hydrazine, or ahydrate thereof, is carried out in a suitable solvent at a suitabletemperature providing a suitable rate of formation of the requiredproduct, generally an elevated temperature, over a suitable reactiontime. A suitable solvent is ethanol. Suitable reaction temperaturesinclude the reflux temperature of the mixture. Suitable reaction timesare those in the range 1–48 hours. The reaction products are isolatedusing conventional methods. Typically, the reaction mixture isconcentrated in vacuo and water added. The product isolated byfiltration, washed, and dried. Conventional methods of heating andcooling may be employed, for example electric heating mantles andice/salt baths respectively. The reaction product may, if desired, bepurified by conventional methods, such as crystallisation,chromatography and trituration.

In a preferred aspect, hydrazine hydrate is added to a stirred solutionof the compound of formula (XVIII) in ethanol. The mixture is stirred atreflux for 4 hours then concentrated in vacuo. Water is added and theproduct isolated by filtration and dried. The crude product may be usedwithout purification.

The compound of formula (XVIII) may be prepared from the compound offormula (XIX),

by reaction with a mixture of phosphorus oxychloride and phosphoruspentachloride.

The reaction between the compound of formula (XIX) and a sure ofphosphorus oxychloride and phosphorus pentachloride is carried out at asuitable temperature providing a suitable rate of formation of therequired product, generally an elevated temperature, over a suitablereaction time. Suitable reaction temperatures include the refluxtemperature of the mixture. Suitable reaction times are those in therange 1–48 hours. The reaction products are isolated using conventionalmethods. Typically, the reaction mixture is cooled and added cautiouslyto iced water. The product isolated by filtration, washed, and dried invacuo. Conventional methods of heating and cooling may be employed, forexample electric heating mantles and ice/salt baths respectively. Thereaction product may, if desired, be purified by conventional methods,such as crystallisation, chromatography and trituration.

In a preferred aspect, the compound of formula (XIX) is added to asuspension of phosphorus oxychloride and phosphorus pentachloride. Thesuspension is stirred at reflux for 3 hours, cooled, and cautiouslyadded to iced water. The product isolated by filtration, washed withwater, and dried in vacuo. The crude product may be used withoutpurification.

The compound of formula (XIX) is believed to be novel and accordinglyforms a further aspect of the invention.

The compound of formula (XIX) may be prepared from the compound offormula (XX),

by reaction with bromine.

The reaction between the compound of formula (XX) and bromine is carriedout in a suitable solvent at a suitable temperature providing a suitablerate of formation of the required product, generally ambienttemperature, over a suitable reaction time. A suitable solvent is aceticacid. Suitable reaction times are those in the range 12–24 hours. Thereaction products are isolated using conventional methods. Typically,the reaction mixture is concentrated in vacuo and the resulting oiltriturated with a suitable solvent. A suitable solvent for triturationis ethanol. The reaction product may, if desired, be purified byconventional methods, such as crystallisation, chromatography andtrituration.

In a preferred aspect, bromine is added to a solution of the compound offormula (XX) in acetic acid. The suspension is stirred for 14 hours,concentrated in vacuo, and the resulting oil triturated with ethanol.The crude product may be used without purification.

The compound of formula (XX) is prepared by procedures disclosed in J.Heterocycl. Chem., 1985, 22, 771.

Compounds of formula (VII) may be prepared from compounds of formula (V)by conventional methods of preparing boronic acids or esters thereof,for example those discloed in standard reference texts of syntheticmethodology such as J. March, Advanced Organic Chemistry, 3rd Edition(1985), Wiley Interscience.

An example of the preparation of a compound of formula (VII) involvesthe reaction of a compound of formula (I) with bis(pinacolato)diboron ina suitable degassed solvent in the presence of a suitable catalyst and asuitable base at a suitable temperature providing a suitable rate offormation of the required product, generally an elevated temperature,over a suitable reaction time. Suitable solvents include DMSO. Suitablecatalysts include [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride. Suitable bases include potassium acetate. Suitable reactiontemperatures include those in the range of 60° C. to 220° C. and, asappropriate, the reflux temperature of the solvent. Suitable reactiontimes are those in the range 8–24 hours. The reaction products areisolated using conventional methods. Typically, the reaction mixture iscooled, filtered through diatomaceous earth, and diluted with ethylacetate, and washed with brine. The organic layer is isolated, dried andevaporated. Conventional methods of heating and cooling may be employed,for example electric heating mantles and ice/salt baths respectively.The reaction products are purified by conventional methods, such ascrystallisation, chromatography and trituration. Crystalline product maybe obtained by standard methods.

Compounds of formulae (I), (II), (V), (VII), (XI), (XIII), (XIV), (XVII)(XIX) and (XX) may exist as tautomers. The present invention encompassesall tautomeric forms of the compounds of formulae (I), (II), (V), (VII),(XI), (XIII), (XIV), (XVII) (XIX) and (XX).

Compounds of formulae (III), (VI), (VIII)–(XVIII) and (XX) are eithercommercially available or are prepared by analogy with knownconventional literature procedures, for example those disclosed in J.Med Chem 1989, 32, 528, J Med Chem 1999, 42, 730 or in standardreference texts of synthetic methodology such as J. March, AdvancedOrganic Chemistry, 3rd Edition (1985), Wiley Interscience.

As stated above, the compounds of formula (I), or pharmaceuticallyacceptable derivatives thereof, are indicated to be useful as inhibitorsof glycogen synthase kinase-3.

The invention therefore provides a compound of formula (I), or apharmaceutically acceptable derivative thereof, for use as an inhibitorof GSK-3.

Accordingly, the present invention also provides a method for thetreatment of conditions associated with a need for inhibition of GSK-3such as diabetes, conditions associated with diabetes, chronicneurodegenerative conditions including dementias such as Alzheimer'sdisease, Parkinson's disease, progressive supranuclear palsy, subacutesclerosing panencephalitic parkinsonism, postencephalitic parkinsonism,pugilistic encephalitis, guam parkinsonism-dementia complex, Pick'sdisease, corticobasal degeneration, frontotemporal dementia,Huntingdon's disease, AIDS associated dementia, amyotrophic lateralsclerosis, multiple sclerosis and neurotraumatic diseases such as acutestroke, mood disorders such as schizophrenia and bipolar disorders,promotion of functional recovery post stroke, cerebral bleeding (forexample, due to solitary cerebral amyloid angiopathy), hair loss,obesity, atherosclerotic cardiovascular disease, hypertension,polycystic ovary syndrome, syndrome X, ischaemia, traumatic braininjury, cancer, leukopenia, Down's syndrome, Lewy body disease,inflammation, and immunodeficiency, which method comprises theadministration of a pharmaceutically effective, non-toxic amount of acompound of formula (I) or a pharmaceutically acceptable derivativethereof,

The present invention further provides a compound of formula (I), or apharmaceutically acceptable derivative thereof, for use as an inhibitorof glycogen synthase kinase-3, and especially for use in the treatmentof conditions associated with a need for the inhibition of GSK-3, suchas diabetes, conditions associated with diabetes, chronicneurodegenerative conditions including dementias such as Alzheimer'sdisease, Parkinson's disease, progressive supranuclear palsy, subacutesclerosing panencephalitic parkinsonism, postencephalitic parkinsonism,pugilistic encephalitis, guam parkinsonism-dementia complex, Pick'sdisease, corticobasal degeneration, frontotemporal dementia,Huntingdon's disease, AIDS associated dementia, amyotrophic lateralsclerosis, multiple sclerosis and neurotraumatic diseases such as acutestroke, mood disorders such as schizophrenia and bipolar disorders,promotion of functional recovery post stroke, cerebral bleeding (forexample, due to solitary cerebral amyloid angiopathy), hair loss,obesity, atherosclerotic cardiovascular disease, hypertension,polycystic ovary syndrome, syndrome X, ischaemia, traumatic braininjury, cancer, leukopenia, Down's syndrome, Lewy body disease,inflammation, and immunodeficiency.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable derivative thereof, for themanufacture of a medicament for the treatment of conditions associatedwith a need for the inhibition of GSK-3, such as diabetes, conditionsassociated with diabetes, chronic neurodegenerative conditions includingdementias such as Alzheimer's disease, Parkinson's disease, progressivesupranuclear palsy, subacute sclerosing panencephalitic parkinsonism,postencephalitic parkinsonism, pugilistic encephalitis, guamparkinsonism-dementia complex, Pick's disease, corticobasaldegeneration, frontotemporal dementia, Huntingdon's disease, AIDSassociated dementia, amyotrophic lateral sclerosis, multiple sclerosisand neurotraumatic diseases such as acute stroke, mood disorders such asschizophrenia and bipolar disorders, promotion of functional recoverypost stroke, cerebral bleeding (for example, due to solitary cerebralamyloid angiopathy), hair loss, obesity, atherosclerotic cardiovasculardisease, hypertension, polycystic ovary syndrome, syndrome X, ischaemia,traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy bodydisease, inflammation, and immunodeficiency.

In a further aspect of this invention, there is provided a compound offormula (I), or a pharmaceutically acceptable derivative thereof, foruse as an active therapeutic substance.

Preferably, the compounds of formula (I), or pharmaceutically acceptablederivatives thereof, are administered as pharmaceutically acceptablecompositions.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises a compound of formula (I), or a pharmaceuticallyacceptable derivative thereof, and a pharmaceutically acceptablecarrier.

Neurotraumatic diseases include both open or penetrating head trauma,such as caused by surgery, or a closed head trauma injury, such ascaused by an injury to the head region, ischaemic stroke including acutestroke, particularly to the brain area, transient ischaemic attacksfollowing coronary by-pass and cognitive decline following othertransient ischaemic conditions.

The active compounds are usually administered as the sole medicamentagent but they may be administered in combination with other medicamentagents as dictated by the severity and type of disease being treated.For example in the treatment of diabetes, especially Type 2 diabetes, acompound of formula (I), or a pharmaceutically acceptable derivativethereof, may be used in combination with other medicament agents,especially antidiabetic agents such as insulin secretagogues, especiallysulphonylureas, insulin sensitisers, especially glitazone insulinsensitisers (for example thiazolidinediones), or with biguanides oralpha glucosidase inhibitors or the compound of formula (I), or apharmaceutically acceptable derivative thereof, may be administered incombination with insulin.

The said combination comprises co-administration of a compound offormula (I), or a pharmaceutically acceptable derivative thereof, and anadditional medicament agent or the sequential administration of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, and the additional medicament agent.

Co-administration includes administration of a pharmaceuticalcomposition which contains both a compound of formula (I), or apharmaceutically acceptable derivative thereof, and the additionalmedicament agent or the essentially simultaneous administration ofseparate pharmaceutical compositions of a compound of formula (I), or apharmaceutically acceptable derivative thereof, and the additionalmedicament agent.

The compositions of the invention are preferably adapted for oraladministration. However, they may be adapted for other modes ofadministration. The compositions may be in the form of tablets,capsules, powders, granules, lozenges, suppositories, reconstitutablepowders, or liquid preparations, such as oral or sterile parenteralsolutions or suspensions. In order to obtain consistency ofadministration it is preferred that a composition of the invention is inthe form of a unit dose. Preferably the composition are in unit dosageform. A unit dose will generally contain from 0.1 to 1000 mg of theactive compound.

Generally an effective administered amount of a compound of theinvention will depend on the relative efficacy of the compound chosen,the severity of the disorder being treated and the weight of thesufferer. However, active compounds will typically be administered onceor more times a day for example 2, 3 or 4 times daily, with typicaltotal daily doses in the range of from 0.1 to 800 mg/kg/day.

Suitable dose forms for oral administration may be tablets and capsulesand may contain conventional excipients such as binding agents, forexample syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (whichmay include edible oils), for example almond oil, fractionated coconutoil, oily esters such as esters of glycerine, propylene glycol, or ethylalcohol; preservatives, for example methyl or propyl p-hydroxybenzoateor sorbic acid; and if desired conventional flavouring or colouringagents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The formulations mentioned herein are carried out using standard methodssuch as those described or referred to in reference texts such as theBritish and US Pharmacopoeias, Remington's Pharmaceutical Sciences (MackPublishing Co.), Martindale The Extra Pharmacopoeia (London, ThePharmaceutical Press) or the above-mentioned publications.

Suitable methods for preparing and suitable unit dosages for theadditional medicament agent, such as the antidiabetic agent mentionedherein include those methods and dosages described or referred to in theabove-mentioned reference texts.

GSK-3 Assay

GSK-3 assays used to test the compounds of the invention include thefollowing protocol which is based on the ability of the kinase tophosphorylate a biotinylated 26 mer peptide,Biot-KYRRAAVPPSPSLSRHSSPHQ(S)EDEEE, the sequence of which is derivedfrom the phosphorylation site of glycogen synthase, where (S) is apre-phosphorylated serine as in glycogen synthase in vivo and the threeconsensus sites for GSK-3 specific phosphorylation are underlined. Thephosphorylated biotinylated peptide is then captured onto Streptavidincoated SPA beads (Amersham Technology), where the signal from the ³³P isamplified via the scintillant contained in the beads.

Using microtitre plates, GSK-3 was assayed in 50 mM MOPS buffer, pH 7.0,containing 5% glycerol, 0.01% Tween-20, 7.5 mM 2-mercaptoethanol, 10 mMmagnesium acetate, 8 uM of the above peptide, and 10 uM [³³P]-ATP. Afterincubation at room temperature, the reaction was stopped by addition of50 mM EDTA solution containing the Streptavidin coated SPA beads to givea final 0.2 mgs. Following centrifugation, the microtitre plates arecounted in a Trilux 1450 microbeta liquid scintillation counter(Wallac). IC₅₀ values are generated for each compound by fitting to afour parameter model.

The most potent compounds of the present invention show IC₅₀ values inthe range of 1 to 500 nM.

No adverse toxicological effects are expected for the compounds of theinvention, when administered in accordance with the invention.

The following Descriptions and Examples illustrate the invention, but donot limit it in any way. Examples 1–151 are pyrazolo[3,4-b]pyridinederivatives and Examples 152–307 are pyrazolo[3,4-c]pyridazinederivatives.

SYNTHETIC METHOD A EXAMPLE 1N-(5-Phenyl-1H-pyrazolo[3,4-b]pyridin-3-yl)butyramide

n-Butyryl chloride (40 μl, 0.36 mmol) was added to a solution of5-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine (Description 2; 100 mg,0.47 mmol) in pyridine (0.5 ml). The reaction mixture was stirred atreflux for 16 hours, then allowed to cool. The solution was acidified topH 1 with 5N HCl, and the resulting solids were filtered and dried.Crystallization from DMF/MeOH afforded the title compound as a solid.

MS calculated for (C₁₆H₁₆N₄O+H)⁺: 281. Found: 281. ¹H NMR δ (d6 DMSO)13.3 (s, 1H), 10.7 (s, 1H), 8.8 (1H, s), 8.6 (s, 1H), 7.7 (d, 2H), 7.5(appt, 2H), 7.4 (d, 1H), 2.4 (t, 2H), 1.6 (td, 2H), 0.9 (t, 3H).

The starting material for Example 1 may be prepared according toDescription 1 and Description 2 below.

Description 1 2-Chloro-5-phenylnicotinonitrile

2-Oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (2.50 g, 12.7 mmol)was added to a suspension of POCl₃ (1.5 ml) and PCl₅ (7.35 g) at roomtemperature. The suspension was then stirred at reflux for 1 hour. Thereaction mixture was cooled to room temperature and added cautiously toiced water. The solution was then adjusted to pH 11 with sodiumcarbonate and the resulting white solid was filtered, washed with water,then dried in vacuo to afford the title compound as a solid.

¹H NMR δ (d6 DMSO) 8.8 (d, 1H), 8.2 (d, 1H), 7.6–7.5 (m, 5H).

Description 2 5-Phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine

Hydrazine hydrate (1.42 g, 28 mmol) was added to a stirred solution of2-chloro-5-phenylnicotinonitrile (2.45 g, 11.4 mmol) in pyridine (25ml). The reaction mixture was stirred at reflux for 6 hours, cooled andthe resulting solid was filtered and dried in vacuo, affording the titlecompound as a solid.

¹H NMR δ (d6 DMSO) 12.0 (br, 1H), 8.7 (d, 1H), 8.4 (d, 1H), 7.7 (d, 2H),7.5 (appt, 2H), 7.4 (d, 1H), 5.6 (s, 2H).

SYNTHETIC METHOD B EXAMPLE 2N-(5-Pyridin-3-yl-1H-pyrazolo[3,4-b]pyridin-3-yl)butyramide

Pd(PPh₃)₄ (30 mg) was added to a degassed solution ofN-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl-butyramide (Description 6; 150mg, 0.5 mmol), 3-pyridyl boronic acid (95 mg, 0.8 mmmol), aq. Na₂CO₃(0.75 ml, 2M) in ethanol (0.75 ml) and DMF (1.5 ml). The mixture wasstirred at reflux for 12 hours, cooled and then water was added. Theresulting solids were filtered and purified by column chromatography (5%MeOH/CHCl₃) affording the title compound as a powder.

LC/MS 100%, MS calcd for (C₁₅H₁₅N₅O+H)⁺: 282. Found: 282. ¹H NMR δ (d6DMSO) 13.3 (s, 1H), 10.8 (s, 1H), 8.9 (1H, s), 8.8 (s, 1H), 8.6 (s, 1H),8.6 (d, 1H), 8.1 (d, 1H), 7.5 (dd, 1H), 2.4 (t, 2H), 1.6 (td, 2H), 0.9(t, 3H).

The starting material for Example 2 may be prepared according toDescriptions 3–6 below.

Description 3 5-Bromo-2-oxo-1,2-dihydro-pyridine-3-carbonitrile

Bromine (29 ml, 560 mmol) was added to a stirred solution of2-oxo-1,2-dihydro-pyridine-3-carbonitrile (34 g, 280 mmol) in aceticacid (180 ml) at room temperature. After 14 hours the reaction mixturewas concentrated in vacuo and the resulting oil was trituated withethanol to afford the title compound as a solid.

¹H NMR δ (d6 DMSO) 12.8 (brs, 1H), 8.4 (d, 1H), 8.1 (d, 1H).

Description 4 5-Bromo-2-chloro-nicotinonitrile

5-Bromo-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (33 g, 166 mmol) wasadded to a suspension of PCl₅ (96.6 g, 464 mmol) in POCl₃ (20 ml, 216mmol). The mixture was stirred at reflux for 3 hours, cooled to roomtemperature and then poured slowly into ice/water. The resulting solidwas fitered, washed with water, and dried in vacuo to afford the titlecompound.

¹H NMR δ (d6 DMSO) 8.7 (d, 1H), 8.1 (d, 1H).

Description 5 5-Bromo-1H-pyrazolo[3,4-b]pyridin-3-ylamine

Hydrazine hydrate (19 ml, 391 mmol) was added to a stirred solution of5-bromo-2-chloronicotinonitrile (34 g, 156 mmol) in ethanol (300 ml).The reaction mixture was stirred at reflux for 4 hours then the solventwas removed in vacuo. Water was added and the resulting solids werefiltered, washed with water, and dried in vacuo to afford the titlecompound as a solid.

¹H NMR δ (d6 DMSO) 12.2 (s, 1H), 8.4 (appd, 2H), 5.7 (s, 2H).

Description 6 N-(5-Bromo-1H-pyrazolo[3,4-b]pyridin-3-yl-butyramide

Butyryl chloride (2.1 ml, 20.7 mmol) was added to a stirred solution of5-bromo-1H-pyrazolo[3,4-b]pyridin-3-ylamine (4.0 g, 18.8 mmol) inpyridine (50 ml). The solution was heated at reflux for 12 hours thenconcentrated in vacuo. Addition of water afforded a solid which wasfiltered and dried to afford the title compound.

LC/MS 100%, MS calcd for (C₁₀H₁₁BrN₄O+H)⁺: 284. Found: 284. ¹H NMR δ (d6DMSO) 13.4 (s, 1H), 10.8 (s, 1H), 8.6 (1H, s), 8.5 (s, 1H), 2.4 (t, 2H),1.6 (td, 2H), 0.9 (t, 3H).

SYNTHETIC METHOD C EXAMPLE 561-[4-(5-Phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylcarbamoyl)butyl]pyridiniumbromide

Oxalyl chloride (0.1 mL, 1.2 mmol) was added to a solution of5-bromovaleric acid (86 mg, 0.48 mmol) in dichloromethane (10 mL).N,N-Dimethylformamide (1 drop) was added and the mixture was stirred atambient temperature for 16 hours. The solvent was removed under vacuum,the residue was azeotroped with toluene (3×30 mL) and evaporated todryness. To this crude acid chloride was added5-phenyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine (Description 2; 100 mg,0.48 mmol), pyridine (20 mL). and 4-dimethylaminopyridine (cat). Thesolution was refluxed at 120° C. for 16 hours then evaporated. Theresidual material was purified by preparative HPLC on a C18 column,using a gradient elution with 10–90% v/v of acetonitrile (containing0.01% v/v trifluoroacetic acid) and water (containing 0.1% v/vtrifluoroacetic acid) to afford the title compound.

¹H NMR δ (CD₃OD): 1.84 (2H, m), 2.18 (2H, m), 2.65 (2H, t), 4.73 (2H,t), 7.42 (1H, m), 7.51 (2H, t), 7.68 (2H, d), 8.12 (2H, t), 8.60 (1H,s), 8.60 (1H, t), 8.76 (1H, d), 9.05 (2H, d). NH protons are assumed tohave exchanged with the solvent. MS (APCI+ve): [M]⁺ at m/z 372(C₂₂H₂₂N₅O requires [M]⁺ at m/z 372).

SYNTHETIC METHOD D EXAMPLE 65 Cyclopropanecarboxylic acid(5-pyridin-3-yl-1H-pyrazolo[3,4-b]pyridin-3-yl)amide Hydrochloride Salt

Tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) was added toa stirred and degassed solution of cyclopropanecarboxylic acid[5-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]amide(Description 7; 200 mg, 0.61 mmol), 3-bromopyridine (193 mg, 1.22 mmol)and potassium acetate (179 mg, 1.83 mmol) in DMF (2 mL), EtOH (1 mL) andH₂O (1 mL) and the reaction mixture was stirred at 100° C. for 18 h. Thereaction mixture was dissolved in EtOAc (100 mL) and washed withsaturated aqueous sodium bicarbonate solution (100 mL) and brine (100mL). The organic extracts were dried (magnesium sulfate) andconcentrated. The crude residue was triturated with dichloromethane anda white solid was obtained. This solid was treated with hydrogenchloride (g) in diethyl ether to afford the corresponding salt as apowder.

MS calcd for (C₁₅H₁₃N₅O+H)⁺: 280. Found: 280. ¹H NMR δ (D₂O) 8.94 (1H,s), 8.69–8.70 (2H, m), 8.62 (1H, s), 8.39 (1H, s), 8.04–8.07 (1H, dd),1.75 (1H, m), 0.88–0.91 (4H, m). NH signals assumed exchanged withsolvent.

The starting material for Example 65 may be prepared according toDescription 7, below.

Description 7 Cyclopropanecarboxylic acid[5-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]amide

[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride(PdCl₂(dppf)₂; 0.46 g, 0.5 mmol) was added to a stirred and degassedsolution of cyclopropanecarboxylic acid(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)amide (prepared by analogy withDescription 6; 5 g, 17.8 mmol), bis(pinacolato)-diboron (5 g, 19.6 mmol)and potassium acetate (5.2 g, 53.4 mmol) in dry DMSO (50 mL). Thesolution was heated at 100° C. overnight then reaction mixture wasallowed to cool. The reaction mixture was filtered through celite, takenup in EtOAc (200 mL) and washed with brine (3×200 mL). The organicextract was dried (magnesium sulfate) and concentrated to afford a brownsolid. This solid was triturated in EtOAc and filtered to afford thetitle compounds as a powder.

¹H NMR δ (DMSO-d₆) 13.28 (1H, s), 11.02 (1H, s), 8.79 (1H, d), 8.63–8.64(1H, d), 1.96–1.99 (1H, m), 1.33 (12H, s), 0.84–0.87 (4H, m).

SYNTHETIC METHOD E EXAMPLE 128 5-Diethylaminopentanoic acid[5-(2-fluorophenyl)-1H-pyrazolo[3,4-b]-pyridin-3-yl]amideTrifluoroacetate Salt

Oxalyl chloride (0.39 mL, 4.5 mmol) was added to a solution of5-diethylamino-valeric acid (380 mg, 1.81 mmol) in dichloromethane (15mL). N,N-Dimethyl-formamide (1 drop) was added and the mixture wasstirred at ambient temperature for 16 hours. The solvent was removedunder vacuum, azeotroped with toluene (3×30 mL) and evaporated todryness. To this acid chloride was added5-(2-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine (prepared byanalogy with Description 2; 0.05 g, 0.22 mmol) and pyridine (2 mL). Thesolution was refluxed for 16 hours. The mixture was cooled, piperidine(40 mL) was added and the mixture stirred for a further 24 hours atambient temperature. The solvents were removed under vacuum, saturatedaqueous sodium bicarbonate solution (20 mL) was added and the mixtureextracted with ethyl acetate (3×50 mL). The ethyl acetate solution wasevaporated and the residue purified by preparative HPLC on a C18 column,using a gradient elution with 10–90% v/v of acetonitrile (containing0.01% v/v trifluoroacetic acid) and water (containing 0.1% v/vtrifluoroacetic acid) to afford the title compound at thetrifluoroacetate salt.

MS (APCI+ve): [M+H]⁺ at m/z 384 (C₂₁H₂₆N₅OF requires [M+H]⁺ at m/z 384).¹H NMR (DMSO-d₆): 1.20 (6H, t), 1.70 (4H, m), 2.51 (2H, br s), 3.12 (2H,m), 3.13 (4H, m), 7.36 (1H, t), 7.38 (1H, m), 7.48 (1H, m), 7.59 (1H,dt), 8.57 (1H, t), 8.66 (1H, t), 8.93 (1H, br s), 10.69 (1H, br s),13.30 (1H, br s).

Further Examples of pyrazolo[3,4-b]pyridines according to the inventionare illustrated in Table 1. The further examples described herein wereprepared by analogy with Synthetic Methods A and E disclosed

TABLE 1

LC/MS Calculated [M + H]⁺ Observed Molecular (Unless [M]+, [M]− Ex #Synth R1 R2 Weight (M) or [M − H]− are indicated) 1 A n-Pr Ph 280.329281 2 B n-Pr Pyridin-3-yl 281.318 282 3 A CF3 Ph 306.246 307 4 A CH2CF3Ph 320.273 321 5 A Me Ph 252.276 253 6 A Et Ph 266.303 267 7 A n-Bu Ph294.356 295 8 A n-Pentyl Ph 308.383 309 9 A n-Hexyl Ph 322.41 323 10 ACH2OMe Ph 282.302 283 11 A CH2CH2COOH Ph 310.312 311 12 A (E)-CH═CHCH3Ph 278.314 279 13 A CH═CMe2 Ph 292.34 293 14 A (E)-CH═CHPh Ph 340.384341 15 A Ph Ph 314.347 315 16 A 2-Furyl Ph 304.308 305 17 A CH2Ph Ph328.373 329 18 A CH2CH2Ph Ph 342.4 343 19 A CH2CH2CH2NMe2 Ph 323.398 32420 A Pyridin-4-yl Ph 315.335 316 21 A (CH2)3-(Piperidin- Ph 363.462 3641-yl) 22 A (CH2)3(4-Et- Ph 392.504 393 Piperazin-1-yl) 23 A (CH2)3- Ph365.435 366 (Morpholin-4-yl) 24 A N-Me-Piperidin-4- Ph 335.409 336 yl 25A i-Pr Ph 280.329 281 26 A CH2-(Pyridin-3-yl) Ph 329.362 330 27 A2-Thienyl Ph 320.375 321 28 A t-Bu Ph 294.356 295 29 A CH2OPh Ph 344.372345 30 B n-Pr (2-OCH2Ph)-Ph 386.453 387 31 B n-Pr 2-Cl-Ph 314.775315/317 32 B n-Pr 2-F-Ph 298.319 299 33 B n-Pr 2-Me-Ph 294.356 295 34 Bn-Pr 2-OMe-Pyridin-3-yl 311.343 312 35 B n-Pr 2-OMe-Ph 310.355 311 36 Bn-Pr 3,4-[OCH2O]-Ph 324.338 325 37 B n-Pr 3,5-di-Cl-Ph 349.22349/351/353 38 B n-Pr 3-NHCOMe-Ph 337.381 338 39 B n-Pr 3-CF3-Ph 348.326349 40 B n-Pr 3-Cl-Ph 314.775 315/317 41 B n-Pr 3-F-Ph 298.319 299 42 Bn-Pr Furan-3-yl 270.291 271 43 B n-Pr 3-OMe-Ph 310.355 311 44 B n-Pr3-NO2-Ph 325.327 326 45 B n-Pr 3-Thienyl 286.358 287 46 B n-Pr 4-CF3-Ph348.326 349 47 B n-Pr 4-Cl-Ph 314.775 315/317 48 B n-Pr 4-F-Ph 298.319299 49 B n-Pr 4-OMe-Ph 310.355 311 50 B n-Pr 4-Me-Ph 294.356 295 51 Bn-Pr 4-OCF3-Ph 364.325 365 52 B n-Pr Indol-5-yl 319.366 320 53 B n-Pr4-OMe-Pyridin-3-yl 311.343 312 54 A n-Pr 2,3-di-F-Ph 316.31 317 55 A(CH2)3- 2,3-di-F-Ph 401.415 402 (Morpholin-4-yl) 56 C (CH2)4-(1- Ph372.45 372 [M]+ Pyridinium) bromide 57 A Et 2,3-di-F-Ph 302.283 303 58 Ai-Pr 2,3-di-F-Ph 316.31 317 59 B n-Pr 2-(CHO)-Ph 308.339 309 60 B n-PrPyridin-4-yl 281.318 282 61 B n-Pr Furan-2-yl 270.291 271 62 B n-PrBiphenyl-4-yl 356.427 357 63 B n-Pr Naphthalen-1-yl 330.389 331 64 Bn-Pr 3-(CHO)-Ph 308.339 309 65 D cyclo-Pr Pyridin-3-yl 279.302 280 66 Dn-Pr 2,3,4-tri-F-Ph 334.300 335 67 D n-Pr 2,4,5-tri-F-Ph 334.300 335 68D n-Pr 3,4,5-tri-F-Ph 334.300 335 69 D n-Pr 2,3,5-tri-F-Ph 334.300 33570 D n-Pr 2,4,6-tri-F-Ph 334.300 335 71 D n-Pr 2,6-di-Cl-Ph 349.220347/349/351 [M − H]− 72 D n-Pr Pyrimidin-2-yl 282.306 281 [M − H]− 73 Dn-Pr Pyrimidin-5-yl 282.306 281 [M − H]− 74 D n-Pr Quinolin-3-yl 331.377332 75 A cyclo-Pr 2,3-di-F-Ph 314.294 315 76 A cyclo-Bu 2,3-di-F-Ph328.321 329 77 A (CH2)3-meso-3,5- 2,3-di-F-Ph 429.469 430di-Me-Morpholin-4- yl) 78 D n-Pr 2,5-di-F-Ph 316.31 317 79 D n-Pr3,5-di-F-Ph 316.31 317 80 A cyclo-Pentyl Ph 306.367 307 81 A cyclo-Pr Ph278.314 279 82 A cyclo-Bu Ph 292.34 293 83 A CHEt2 Ph 308.383 309 84 Acyclo-Hexyl Ph 320.394 321 85 D n-Pr 3,4-di-F-Ph 316.310 317 86 D n-Pr2,6-di-F-Ph 316.310 317 87 D n-Pr 2,3,6-tri-F-Ph 334.300 335 88 A2-Butyl Ph 294.356 295 89 D n-Pr Pyrazin-2-yl 282.306 282 [M]− 90 D n-Pr2,4-di-Cl-Ph 349.22 347/349/351 [M − H]− 91 D n-Pr 2-Cl-4-F-Ph 332.765331/333 [M − H]− 92 D n-Pr 3-CN-Ph 305.34 306 93 D n-Pr 3-CO2H-Ph324.338 325 94 D n-Pr 3-CO2Me-Ph 338.365 339 95 D n-Pr 3-Cl-4-F-Ph332.765 333/335 96 D n-Pr 3-F-4-Cl-Ph 332.765 333/335 97 D n-Pr2,5-di-Cl-Ph 349.220 349/351/353 98 D n-Pr Naphthalen-1-yl 330.389 33199 A C(Me2)Ph Ph 356.427 357 100 D n-Pr 3-OH-Ph 296.328 297 101 D n-Pr4-OH-Ph 296.328 297 102 D n-Pr Pyridin-2-yl 281.318 282 103 D n-Pr2-F-4-Cl-Ph 332.765 333/335 104 D n-Pr 4-(OCH2CH2NMe2)-Ph 367.451 368105 D n-Pr 2-(OCH2CH2NMe2)-Ph 367.451 368 106 D n-Pr 2-[O(CH2)3NMe2]-Ph381.477 382 107 D n-Pr 4-[O(CH2)3NMe2]-Ph 381.477 382 108 D n-Pr3-(OCH2CH2NMe2)-Ph 367.451 368 109 D n-Pr 3-[O(CH2)3NMe2]-Ph 381.477 382110 D n-Pr 2-[OCH2CH2-(Morphoiin-4-yl)]-Ph 409.487 410 111 D n-Pr4-[OCH2CH2-(Morpholin-4-yl)]-Ph 409.487 410 112 A 4-NMe2-Ph 2-F-Ph375.405 376 113 D n-Pr 2-[OCH2CH2CH2-(Morpholin-4- 423.514 424 yl)]-Ph114 D n-Pr 4-[OCH2CH2CH2-(Morpholin-4- 423.514 424 yl)]-Ph 115 D n-Pr3-[OCH2CH2-(Morpholin-4-yl)]-Ph 409.487 410 116 D n-Pr3-[OCH2CH2CH2-(Morpholin-4- 423.514 424 yl)]-Ph 117 A 3,4-[OCH2O]-Ph2-F-Ph 376.346 377 118 A 2,4,6-tri-Me-Ph 2-F-Ph 374.417 375 119 D n-Pr2-[CH2-(Morpholin-4-yl)]-Ph 379.461 380 120 D n-Pr3-[CH2-(Morpholin-4-yl)]-Ph 379.461 380 121 D n-Pr4-[CH2-(Morpholin-4-yl)]-Ph 379.461 380 122 D n-Pr2-[CH2CH2-(Morpholin-4-yl)]-Ph 393.488 394 123 D n-Pr3-[CH2CH2-(Morpholin-4-yl)]-Ph 393.488 394 124 D n-Pr4-[CH2CH2-(Morpholin-4-yl)]-Ph 393.488 394 125 D n-Pr 3-NMe2-Ph 323.398324 126 D n-Pr Benzo[b]thiophen-3-yl 336.417 337 127 D Me Pyrazin-2-yl254.252 255 128 E (CH2)4NEt2 2-F-Ph 383.468 384 129 D cyclo-Pr2,5-di-Me-Pyridin-3-yl 307.355 308 130 D cyclo-Pr 4-Me-Pyridin-3-yl293.328 294 131 D cyclo-Pr 2-Cl-S-Me-Pyridin-3-yl 327.774 328/330 132 Dcyclo-Pr 2-Cl-4,5-di-Me-Pyridin-3-yl 341.8 342/344 133 D cyclo-Pr6-NH2-Pyridin-3-yl 294.317 295 134 D cyclo-Pr 2-Me-6-NH2-Pynidin-3-yl308.343 309 135 D cyclo-Pr 6-(NHCONH2)-Pyridin-3-yl 337.341 295 Fragmention [(C15H14N67O) + H]+ 136 D cyclo-Pr 2-NH2-5-Me-Pyridin-3-yl 308.343309 137 D cyclo-Pr 2-Cl-Pyridin-3-yl 313.747 314/316 138 D cyclo-Pr5-(Piperidin-1-yl)-Pyridin-3-yl 362.435 363 139 D cyclo-Pr2-(CH2CN)-Pyridin-3-yl 318.339 319 140 D cyclo-Pr5-Me-6-[NH(CH2)3NHCHO]- 393.449 394 Pyridin-3-yl 141 D cyclo-Pr5-Me-6-NH2-Pyridin-3-yl 308.343 309 142 D cyclo-Pr 6-Cl-Pyridin-3-yl313.747 314/316 143 D cyclo-Pr 5-(COCH2CO2Me)-Pyridin-3-yl 379.374 322Fragment ion [(C17H15N5O2) + H]+ 144 D cyclo-Pr2-(NHCOt-Bu)-Pyridin-3-yl 378.434 379 145 D i-Pr5-Me-6-[NH(CH2)3OH]-Pyridin-3-yl 368.439 369 146 D i-Pr5-OMe-Pyridin-3-yl 311.343 312 147 D i-Pr 5-(CO2Et)-Pyridin-3-yl 353.38354 148 D i-Pr 5-(CONH2)-Pyridin-3-yl 324.342 325 149 D i-Pr6-(Pyrrol-1-yl)-Pyridin-3-yl 346.392 347 150 D i-Pr Pyridin-3-yl 281.318282 151 D i-Pr 5-Ph-Pyridin-3-yl 357.415 358

SYNTHETIC METHOD F EXAMPLE 153N-(5-Phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)butyramide

n-Butyryl chloride (120 μl, 0.73 mmol) was added to a solution of5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (Description 8; 100 mg,0.47 mmol) in pyridine (0.5 mL). The reaction mixture was stirred atreflux for 16 hours, then allowed to cool. The solution was acidified topH 1 with 5N HCl, and the resulting solids were filtered and dried.Purification by column chromatography (5% MeOH/CHCl₃) afforded the titlecompound as a solid.

MS (APCI+ve): [M+H]⁺ at m/z 282 (C₁₅H₁₅N₅O requires [M+H]⁺ 282). ¹NMR δ(DMSO-d₆) 14.0 (1H, s), 11.0 (1H, s), 8.7 (1H, s), 8.0 (2H, d), 7.6–7.4(3H, m), 2.4 (2H, t), 1.7 (appq, 2H) and 1.0 (3H, t).

The starting material for Example 153 may be prepared according toDescription 8 below.

Description 8 5-Phenyl-1H-pyrazolop[3,4-c]pyridazin-3-ylamine

Hydrazine hydrate (0.7 ml, 14.3 mmol) was added to a stirred solution of3-chloro-6-phenyl-pyridazine-4-carbonitrile (cf J. Med. Chem., 1999, 42,730; 1.024 g, 4.7 mmol) in pyridine (10 ml). The reaction mixture wasstirred at reflux for 6 hours, cooled and the resulting solid wasfiltered and dried in vacuo, affording the title compound as a solid.

MS APCI+ve): [M+H]⁺ at m/z 212 (C₁₁H₉N₅ requires [M+H]⁺ at m/z 212). ¹HNMR δ (DMSO-d₆) 12.7 (1H, s), 8.5 (1H, s), 8.1 (2H, d), 7.6–7.4 (3H, m)and 6.0 (2H, s).

SYNTHETIC METHOD G EXAMPLE 1544-Dimethylamino-N-(5-Phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)butyramideHydrochloride Salt

4-Dirmethylaminobutyryl chloride.HCl (6.0 g, 32.3 mmol) was added to asolution of 5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (Description8; 4.0 g, 18.9 mmol) in pyridine (200 ml). The reaction mixture wasstirred at reflux for 16 hours, then allowed to cool and thenconcentrated in vacuo. Purification by column chromatography (5% 2MMeOH—NH₃/CHCl₃) afforded an off white solid. Suspension of the solid inCH₂Cl₂ (50 ml) and treatment with 1M ethereal HCl (200 ml) afforded thetitle compound as a solid.

MS calcd for (C₁₇H₂₀N₆O+H)⁺: 325. Found: 325. ¹H NMR δ (d6 DMSO) 14.0(1H, s), 11.2 (1H, s), 10.7 (1H, s), 8.7 (1H, s), 8.1 (2H, d), 7.6–7.4(3H, m), 3.2 (2H, m), 2.6 (2H, t), 2.5 (6H, s), 2.1–2.0 (2H, m).

SYNTHETIC METHOD H EXAMPLE 174N-[5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]-2,4,6-trimethylbenzamide

2,4,6-Trimethylbenzoyl chloride (0.594 g, 3.24 mmol) was added to asolution of 5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-ylamine(Description 14; 0.400 g, 1.62 mmol) in pyridine (2 mL). The solutionwas heated at reflux for 72 hours, and the solvent then evaporated invacuo. Piperidine (50 mL) was added and the solution stirred at roomtemperature for 16 hours. The mixture was evaporated and the residueazeotroped with ethanol. The crude product was purified firstly bychromatography on silica gel using a gradient elution with 5–20% v/vmethanol in dichloromethane, and subsequently by further chromatographyon silica gel using diethyl ether as eluent to afford the titlecompound, a solid.

MS (APCI+ve): [M+H]⁺ at m/z 394 (C₂₁H₁₇ON₅F₂ requires [M+H]⁺ 394). ¹HNMR (DMSO-d₆) δ2.28 (3H, s), 2.30 (6H, s), 6.95 (2H, s), 7.42 (1H, q),7.58 (1H, m), 7.85 (1H, t), 8.72 (1H, s), 11.43 (1H, s), 14.33 (1H, s).

The starting material for Example 174 may be prepared according toDescriptions 9–14 below.

Description 9 Diethyl2-[2-(2,3-difluorophenyl)-2-oxoethyl]-2-hydroxymalonate

2′,3′-Difluoroacetophenone (10.23 g, 65.6 mmol) and diethyl ketomalonate(15 mL, 98.4 mmol) were stirred at 140° C. for 48 hours. The crudemixture was diluted with toluene and purified by chromatography onsilica gel, eluting with 20% v/v ethyl acetate in hexane to afford thetitle compound as an oil.

¹H NMR (CDCl₃) δ1.30 (6H, t), 3.84 (2H, d), 4.18 (1H, s), 4.31 (4H, q),7.18 (1H, m), 7.39 (1H, q) and 7.62 (1H, t).

Description 10 Ethyl6-(2,3-difluorophenyl)-3-hydroxypyridazine-4-carboxylate

Diethyl 2-[2-(2,3-difluorophenyl)-2-oxoethyl]-2-hydroxymalonate (18.50g, 56.1 mmol) and hydrazine monohydrochloride (4.03 g, 58.8 mmol) werestirred at reflux in ethanol (300 mL) for 96 h, and then evaporated todryness to afford the title compound as a solid.

MS (APCI+ve): [M+H]⁺ at m/z 281 (C₁₃H₁₀F₂N₂O₃ requires [M+H]⁺ 281). ¹HNMR (CDCl₃) δ1.14 (3H, t), 4.45 (2H, q), 7.25 (2H, m), 7.51 (1H, t),8.28 (1H, s) and 11.87(1H, s).

Description 11 6-(2,3-Difluorophenyl)-3-hydroxypyridazine-4-carboxylicacid

Ethyl 6-(2,3-difluorophenyl)-3-hydroxypyridazine-4-carboxylate (8.00 g,28.6 mmol) was stirred in ethanol (275 mL) and treated with a solutionof sodium hydroxide (4.6 g, 115 mmol) in water (175 mL). The mixture wasstirred at reflux for 2 hours, cooled, concentrated in vacuo, dilutedwith water to ca. 350 mL total volume and filtered. Acidification with2M hydrochloric acid gave a precipitate which was filtered off, washedwith water, and thoroughly dried in vacuo at 60° C. to afford the titlecompound as a solid.

MS (APCI−ve): [M−H]⁻ at m/z 251 (C₁₁H₆F₂N₂O₃ requires [M−H]⁻ 251). ¹HNMR (DMSO-d₆) δ7.37 (1H, m), 7.57 (2H, m), 8.28 (1H, d) and 14.3 (2H,broad).

Description 12 3-Chloro-6-(2,3-difluorophenyl)pyridazine-4-carboxamide

6-(2,3-Difluorophenyl)-3-hydroxypyridazine-4-carboxylic acid (3.00 g,11.9 mmol) was treated with phosphoryl chloride (15 mL) and 3 drops ofdry DMF. The mixture was stirred at 80° C. for 4 hours, cooled, andevaporated to dryness. The residue was dissolved in dry THF (50 mL) andadded, with vigorous stirring, to 880 ammonia (200 mL). After 1 hour,the mixture was diluted with water (200 mL) and extracted with ethylacetate. The extract was washed with brine, dried (MgSO₄) and evaporatedto give the title compound as a solid.

MS (APCI+ve): [M+H]⁺ at m/z 270/272 (C₁₁H₆ClF₂N₃O requires [M+H]⁺270/272). ¹H NMR (DMSO-d₆) δ7.44 (1H, q), 7.68 (1H, q), 7.75 (1H, t),8.15 (1H, s), 8.21 (1H, s) and 8.30 (1H, s).

Description 13 3-Chloro-6-(2,3-difluorophenyl)pyridazine-4-carbonitrile

3-Chloro-6-(2,3-difluorophenyl)pyridazine-4-carboxamide (3.03 g, 11.2mmol) was stirred in phosphoryl chloride (30 mL) at reflux for 3 hours,cooled, and evaporated to dryness. The residue was dissolved indichloromethane, washed with saturated sodium hydrogen carbonatesolution, dried (MgSO₄) and evaporated to give the title compound as asolid.

MS (APCI+ve): [M+H]⁺ at ml/z 252/254 (C₁₁H₄ClF₂N₃ requires [M+H]⁺252/254). ¹H NMR (CDCl₃) δ7.33 (1H, m), 7.41 (1H, m), 7.97 (1H, t) and8.23 (1H, s).

Description 145-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-ylamine

3-Chloro-6-(2,3-difluorophenyl)pyridazine-4-carbonitrile (2.82 g, 11.2mmol) and hydrazine hydrate (1.25 mL, 25.8 mmol) were stirred at refluxin ethanol (50 mL) for 1 hour. The mixture was cooled and evaporated todryness. The residue was triturated with water, and the solid wasfiltered off and dried, giving the title compound as a solid.

MS (APCI+ve): [M+H]⁺ at m/z 248 (C₁₁H₇F₂N₅ requires [M+H]⁺ 248). ¹H NMR(DMSO-d₆) δ6.10 (2H, s), 7.39 (1H, q), 7.54 (1H, q), 7.82 (1H, t), 8.46(1H, s) and 12.88 (1H, s).

SYNTHETIC METHOD I EXAMPLE 1864-Diethylaminomethyl-N-[5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]benzamide

4-Diethylaminomethylbenzoyl chloride (0.503 g, 2.43 mmol) was added to asolution of 3-amidno-5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridine(Description 14; 0.200 g, 0.81 mmol) in pyridine (5 mL). The mixture washeated at reflux for 16 hours then the solvent was removed under reducedpressure. The residue was azeotroped, firstly with water and then withethanol. The resulting solid was dissolved in dimethylformamide andpurified initially by preparative HIPLC on a C18 column, using agradient elution with 10–90% v/v of acetonitrile (containing 0.01%trifluoroacetic acid) and water (containing 0.1% trifluoroacetic acid).Subsequent purification by silica gel chromatography using initially 5%v/v methanol in dichloromethane as eluent, followed by 5% v/v 1Nmethanolic ammonia in dichloromethane as eluent afforded the titlecompound, a solid.

MS (APCI+ve): [M+H]⁺ at m/z 437 (C₂₃H₂₂ON₆F₂ requires [M+]⁺ 437). ¹H NMR(DMSO-d₆) δ1.01 (6H, br s), 2.50 (4H, m), 3.65 (2H, br s), 7.41 (1H,dd), 7.51 (2H, d), 7.59 (1H, m), 7.82 (1H, t), 8.06 (2H, d), 8.67 (1H,s), 11.47 (1H, s) and 14.37 (1H, s).

SYNTHETIC METHOD J EXAMPLE 191N-[5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl](1,1-dioxo-1-thiomorpholin-4-yl)butyramide

The hydrochloride salt of 4-(1,1-dioxo-1-thiomorpholin-4-yl)butyrylchloride (1.338 g, 4.848 mmol) was added to a solution of3-amino-5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridine (0.2 g, 0.808mmol) in dry pyridine (10 mL) with 4-dimethylaminopyridine (0.05 g) andthe mixture heated at reflux under argon for 48 hours. After allowing tocool most of the solvent was evaporated in vacuo and the residueazeotroped with ethanol (4×10 mL). The mixture was dissolved in methanoland passed through an SCX column, washing with further methanol toremove some colouration. Basic material containing the product was theneluted from the column with 0.5N ammonia in methanol solution andevaporated to dryness in vacuo. Further purification by columnchromatography on silica gel using a gradient elution of 2–8% v/vmethanol in dichloromethane, followed by preparative HPLC on a C18column, using a gradient elution with 10–90% v/v of acetonitrile(containing 0.01% trifluoroacetic) and water (containing 0.1%trifluoracetic acid) gave the product as the trifluoracetate salt. Asolution of this salt in methanol was passed through an SCX column andfurther washed with methanol (20 mL) and then eluted with 0.5N ammoniain methanol. After evaporation of volatile material in vacuo the productwas obtained as a solid.

MS (APCI+ve): [M+H]⁺ at m/z 451 (C₁₉H₂₀N₆O₃S requires [M+H]⁺ at m/z 451)¹H NMR (DMSO-d₆): δ1.80 (2H, m), 2.40–2.60(4H, m partly obscured by DMSOsolvent signal), 2.88 (4H, m), 3.03 (4H, m), 7.35–7.50 (1H, m),7.50–7.65 (1H, m), 7.81 (1H, t), 8.71 (1H, d), 11.10 (1H, s) and 14.21(1H, s).

SYNTHETIC METHOD K EXAMPLE 219 Piperidine-4-carboxylic acid[5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-cipyridazin-3-yl]-amide

A mixture of 1-benzyl-piperidine-4carboxylic acid[5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-yl]-amide (Example209; 340 mg, 0.76 mmol), ammonium formate (191 mg, 3.03 mmol) and 10%Pd/C (50 mg) in ethanol (10 mL) was stirred at reflux for 72 h. Thereaction mixture was cooled, filtered through celite and concentrated.The residue was purified by chromatography on silica gel using initially10% v/v methanol in dichloromethane and rising to 10% v/v 2N methanolicammonia in dichloromethane to afford the title compound, a powder.

MS (APCI+ve): [M+H]⁺ at m/z 359 (C₁₇H₁₆F₂N₆O requires [M+H]⁺ 359. ¹H NMR(DMSO-d₆) δ11.11 (1H, s), 8.69 (1H, s), 7.79–7.82 (1H, dd), 7.54–7.60(1H, dd), 7.38–7.44 (1H, dd); 3.15–3.18 (2H, t), 2.70–2.75 (2H, t),2.46–2.50 (1H, m), 1.82–1.87 (2H, m); 1.67–1.72 (2H, m). Remaining NHsignals presumed exchanged with solvent

SYNTHETIC METHOD L EXAMPLE 251N-(5-Phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-3-(6-methylpyridin-3-yl)propionamidehydrochloride salt

3-Amino-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Description 8; 0.15 g,0.709 mmol was added to the hydrochloride salt of3-(6-methylpyridin-3-yl)propionyl chloride (0.624 g, 2.84 mmol) in drypyridine (10 mL) and the mixture heated at reflux overnight. Afterevaporation to dryness under reduced pressure and further drying underhigh vacuum the residue was chromatographed on silica gel initially witha gradient elution of 0–10% v/v methanol in dichloromethane, then with agradient of 5–10% v/v 1N ammonia-methanol in dichloromethane. Fractionscontaining product were further purified by preparative HPLC on a C18column, using-a gradient elution with 10–90% v/v acetonitrile(containing 0.01% v/v trifluoroacetic acid) and water (containing 0.1%v/v trifluoracetic acid) to give product as the trifluoroacetate salt. Asolution of this salt in methanol was passed through an SCX column andwashed with methanol (20 mL). The free base of the title compound wasobtained after elution with 66% v/v. 2N methanolic ammonia in methanoland evaporation to dryness. A solution of the free base indichloromethane (10 mL) was then treated with a slight excess of INhydrochloric acid in diethyl ether to give the product as a solid afterevaporation of solvents.

MS (APCI+ve): [M+H]⁺ at m/z 359 (C₂₀H₁₈N₆O requires [M+H]⁺ at mn/z 359)¹H NMR (DMSO-d⁶): δ2.69 (3H, s), 2.91 (2H, t), 3.16 (2H, t), 7.45–7.65(3H, m), 7.86 (1H, d), 8.07 (2H, d), 8.43 (1H, dd), 8.63 (1H, s), 8.75(1H, d), 11.16 (1H, s) and 14.10 (1H, br s). Chemical shifts consistentwith pyridinium salt, but HCl salt proton not seen—presumed exchangedwith solvent.

Further Examples of pyrazolo[3,4-c]pyridazines according to theinvention are illustrated in Table 2. The further examples describedherein were prepared by analogy with Synthetic Methods F–L disclosedabove.

TABLE 2 (I)

LC/MS Calculated [M + H]⁺ Observed Example Synthetic Molecular (Unless[M]+, [M]− No. Method R1 R2 Weight (M) or [M − H]− are indicated) 152 FMe Ph 253.264 254 153 F n-Pr Ph 281.318 282 154 G (CH2)3NMe2 Ph 324.386325 155 G (CH2)3(Morpholin-4-yl) Ph 366.423 367 156 F i-Pr Ph 281.318282 157 F i-Pr 2,3-di-F-Ph 317.298 318 158 F Me 2,3-di-F-Ph 289.244 290159 F Me 2-Cl-Ph 287.709 288/290 160 F i-Pr 2-Cl-Ph 315.763 316/318 161G (CH2)3(Marpholin-4-yl) 2,3-di-F-Ph 402.403 403 162 G Me Pyridin-3-yl254.252 255 163 F cyclo-Pentyl 2-Cl-Ph 341.8 342/344 164 G (CH2)3NMe22-Cl-Ph 358.831 359/361 165 G (CH2)3NMe2 Pyridin-3-yl 325.374 326 166 G(CH2)3NMe2 2,3-di-F-Ph 360.366 361 167 F cyclo-Pentyl Ph 307.355 308 168G (CH2)3(Piperidin-1-yl) 2-Cl-Ph 398.896 399/401 169 F cyclo-Pr Ph279.302 280 170 G (CH2)3NEt2 2-Cl-Ph 386.885 387/389 171 F cyclo-Pr2-Cl-Ph 313.747 314/316 172 F cyclo-Pr 2,3-di-F-Ph 315.282 316 173 Fcyclo-Pr Pyridin-3-yl 280.29 281 174 H 2,4,6-tri-Me-Ph 2,3-di-F-Ph393.395 394 175 G i-Pr Pyridin-2-yl 282.306 283 176 G(CH2)3(Pyrrolidin-1-yl) 2,3-di-F-Ph 386.404 387 177 G cyclo-PrPyridin-2-yl 280.29 281 178 G i-Pr Pyridin-3-yl 282.306 283 179 GN-Me-Piperidin-4-yl Ph 336.397 337 180 G N-Me-Piperidin-4-yl 2,3-di-F-Ph372.377 373 181 G Ph 2,3-di-F-Ph 351.315 352 182 G(CH2)3(Piperidin-1-yl) 2,3-di-F-Ph 400.431 401 183 G(CH2)3(4-Et-Piperazin-1- 2,3-di-F-Ph 429.473 430 yl) 184 G(CH2)3(Pyrrolidin-1-yl) Ph 350.424 351 185 G (CH2)3(Piperidin-1-yl) Ph364.451 365 186 I 4-(CH2NEt2)-Ph 2,3-di-F-Ph 436.464 437 187 I 4-NMe2-Ph2-Cl-Ph 392.848 393/395 188 G (CH2)3(4-Et-Piperazin-1- Ph 393.492 394yl) 189 G cyclo-Pentyl 2,3-di-F-Ph 343.336 344 190 G (CH2)3NEt22,3-di-F-Ph 388.42 389 191 J (CH2)3(1,1-dioxo-1- 2,3-di-F-Ph 450.468 449thiomorpholin-4-yl) [M − H]− 192 I 4-NMe2-Ph 2,3-di-F-Ph 394.383 395 193I 4-NMe2-Ph Ph 358.403 359 194 G (CH2)4NEt2 2,3-di-F-Ph 402.447 403 195G (CH2)4NEt2 Ph 366.466 367 196 G [1-(CH2CH2OMe)- Ph 380.45 381Piperidin-4-yl] 197 G [1-(CH2CH2OMe)- 2,3-di-F-Ph 416.43 417Piperidin-4-yl] 198 I 2,3-Dihydrobenzofuran-5-yl 2,3-di-F-Ph 393.352 394199 F CH2OMe 2,3-di-F-Ph 319.27 320 200 F CH2OMe Ph 283.29 284 201 G(CH2)3NEt2 Ph 352.44 353 202 I [4-[CH2(Pyrrolidin-1-yl)]- 2,3-di-F-Ph434.448 435 Ph)9 203 G (N-Et-Piperidin-4-yl) Ph 350.424 351 204 G(N-Et-Piperidin-4-yl) 2,3-di-F-Ph 386.404 387 205 F CH2CH2OMe2,3-di-F-Ph 333.297 334 206 G iPr 3-Me-Ph 295.344 296 207 F cyclo-Pr3-Me-Ph 293.328 294 208 F CH2O(CH2)2OMe 2,3-di-F-Ph 363.323 364 209 G(1-CH2Ph-Piperidin-4-yl) 2,3-di-F-Ph 448.475 449 210 F CH2OPh Ph 345.361346 211 F CH2O(CH2)2OMe Ph 327.342 328 212 G (CH2)4(Piperidin-1-yl) Ph378.477 379 213 F CH2CH2OMe Ph 297.316 298 214 G (CH2)3N[(CH2)2OMe]2 Ph412.491 413 215 G [1-((CH2)2OPh]-Piperidin- Ph 442.52 443 4-yl] 216 G[1-[(CH2)2OPh]-Piperidin- 2,3-di-F-Ph 478.501 479 4-yl] 217 F CH2OPh2,3-di-F-Ph 381.341 380 [M − H]− 218 I 4-F-Ph 2,3-di-F-Ph 369.305 370219 K Piperidin-4-yl 2,3-di-F-Ph 358.35 359 220 G CH2O-(3-NMe2-Ph)2,3-di-F-Ph 424.409 425 221 G (CH2)3[4-SO2Me- Ph 443.53 444Piperazin-1-yl] 222 G (CH2)3N[(CH2)2OMe]2 2,3-di-F-Ph 448.471 449 223 G(CH2)3[4-SO2Me- 2,3-di-F-Ph 479.51 480 Piperazin-1-yl] 224 G(CH2)3(Pyzrolidin-1-yl) 2,3-di-F-Ph 386.404 387 225 G[1-[(CH2)2O(4-Cl-Ph)]- Ph 476.965 477 Piperidin-4-yl) 226 G[1-[(CH2)2O(4-Cl-Ph)]- 2,3-di-F-Ph 512.946 513 Piperidin-4-yl] 227 Fi-Pr Quinolin-3-yl 332.365 333 228 G CH2O-(3-NMe2-Ph) Ph 388.429 389 229F cyclo-Pentyl Quinolin-3-yl 358.403 359 230 G (CH2)3[4-(CH2Ph)- Ph455.563 456 Piperazin-1-yl] 231 F cyclo-Pr 2-Cl-3-F-Ph 331.737 332/334232 F CH2OMe 2,3-di-F-Ph 333.297 334 233 F i-Pr 2-Cl-3-F-Ph 333.753334/336 234 G (CH2)3N(Me)(CH2)2OMe 2,3-di-F-Ph 404.419 405 235 G[1-[CH2-(4-Cl-Ph)]- Ph 446.94 447 Piperidin-4-yl] 236 G[1-[CH2-(4-Cl-Ph)]- 2,3-di-F-Ph 482.92 483 Piperidin-4-yl] 237 G(CH2)4(Piperidin-1-yl) 2,3-di-F-Ph 414.458 415 238 G (CH2)3[4-(CH2Ph)-2,3-di-F-Ph 491.543 492 Piperazin-1-yl] 239 G N-Me-Piperidin-4-yl2-Cl-3-F-Ph 388.832 389/391 240 I 4-F-Ph Ph 333.325 334 241 G CH2Ph Ph329.362 330 242 F CH2OCH2CF3 2,3-di-F-Ph 387.267 388 243 I2,3-Dihydrobenzofuran-5-yl Ph 357.371 358 244 G [1-[CH2-(4-F-Ph)]- Ph430.485 431 Piperidin-4-yl] 245 G [1-[CH2-(4-F-Ph)]- 2,3-di-F-Ph 466.465467 Piperidin-4-yl] 246 G (CH2)3N(Me)(CH2)2OMe Ph 368.439 369 247 GCH2Ph 2,3-di-F-Ph 365.342 366 248 G CH2-[1-[CH2-(4-F-Ph)]- 2,3-di-F-Ph462.502 463 Piperidin-4-yl] 249 G CH2-[1-[(CH2)2OPh]- 2,3-di-F-Ph492.527 493 Piperidin-4-yl] 250 G rac-[1-(CH2Ph)-Pyrrolidin- 2,3-di-F-Ph434.448 435 3-yl] 251 L (CH2)2-(6-Me-pyridin-3- Ph 358.403 359 yl) 252 L4-[CH2(Pyrrolidin-1-yl)]- Ph 398.468 399 Ph 253 G CH2-[1-[(CH2)2OPh]- Ph456.547 457 Piperidin-4-yl] 254 G CH2-[1-(CH2Ph)-Piperidin- Ph 426.521427 4-yl] 255 G (CH2)3NMe2 2-Cl-3-F-Ph 376.821 377/379 256 GCH2-[1-Et-Piperidin-4-yl] Ph 364.451 365 257 G CH2-[1-Et-Piperidin-4-yl]2,3-di-F-Ph 400.431 401 258 I 4-NMe2-Ph Pyridin-3-yl 359.391 360 259 F(CH2)2Ph 2,3-di-F-Ph 379.368 380 260 G 1-Ph-Piperidin-4-yl Ph 398.468399 261 G 1-Ph-Piperidin-4-yl 2,3-di-F-Ph 434.448 435 262 Ftrans-CH═CH-(4-F-Ph) 2,3-di-F-Ph 395.343 396 263 F (CH2)2(4-F-Ph)2,3-di-F-Ph 397.359 398 264 F trans-CH═CHPh 2,3-di-F-Ph 377.353 378 265L 4-[CH2(Piperidin-1-yl)]-Ph 2,3-di-F-Ph 448.475 449 266 G(CH2)3(Pyrrolidin-1-yl) 2-Cl-3-F-Ph 402.859 403 267 I CH2-(4-NMe2-Ph)2,3-di-F-Ph 408.41 409 268 I (CH2)3[4-[O-(4-Cl-Ph)]- Ph 490.992 491/493piperidin-1-yl] 269 G CH2(1-Ph-Piperidin-4-yl) Ph 412.495 413 270 GCH2(1-Me-Piperidin-4-yl) Ph 350.424 351 271 G CH2(1-Me-Piperidin-4-yl)2,3-di-F-Ph 386.404 387 272 F i-Pr 2,3,6-tri-F-Ph 335.288 336 273 Fcyclo-Pentyl 2,3,6-tri-F-Ph 361.326 362 274 L (CH2)3(4-Et-Piperazin-1-2-Cl-3-F-Ph 445.927 446/448 yl) 275 L CH2-[4-(CH2NMe2)-Ph] 2,3-di-F-Ph408.41 409 276 F cyclo-Pr 2,3,6-tri-F-Ph 333.272 334 277 L(CH2)3(Piperidin-1-yl) 2-Cl-3-F-Ph 416.886 417/419 278 L(CH2)2(6-Me-pyridin-3-yl) 2,3-di-F-Ph 394.383 395 279 Lrac-[(1-CH2Ph)-Pyrrolidin- Ph 398.468 399 3-yl] 280 L[4-(CH2-thiomorpholin-4- 2,3-di-F-Ph 466.514 467 yl)-Ph] 281 L[4-(CH2-thiomorpholin-4- Ph 430.534 431 yl)-Ph] 282 G [1-[CH2-(4-F-Ph)]-2,3,6-tri-F-Ph 484.455 485 Pipenidin-4-yl] 283 L[4-[CH2(Piperidin-1-yl)]- Ph 412.495 413 Ph] 284 L [4-[CH2NEt2]-Ph] Ph400.484 401 285 L (CH2)4(4-Et-Piperazin-1- 2,3-di-F-Ph 443.499 444 yl)286 H cyclo-Pentyl Pyridin-3-yl 308.343 309 287 L[3-[CH2(Pipenidin-1-yl)]- 2,3-di-F-Ph 448.475 449 Ph] 288 L(CH2)3(4-Ph-Piperazin-1- Ph 441.536 442 yl) 289 L (CH2)3(4-[(CH2)2Ph]-Ph 469.59 470 Piperazin-1-yl) 290 L (CH2)3(4-(CH2cyclo- Ph 461.61 462hexyl)-Piperazin-1-yl) 291 L (CH2)4(4-Et-Piperazin-1- Ph 407.519 408 yl)292 G (CH2)3(4-Et-Piperazin-1- 2,3,6-tri-F-Ph 447.463 448 yl) 293 L[3-[CH2(Piperidin-1-yl)]- 2,3-di-F-Ph 434.448 435 Ph] 294 L(CH2)3(4-(cyclo-pentyl)- Ph 433.557 434 Piperazin-1-yl) 295 L(CH2)3(4-iso-Pr-Piperazin- Ph 407.519 408 1-yl) 296 I (CH2)3NMe2 3-Me-Ph338.413 339 297 I (CH2)3(4-Et-Piperazin-1- 3-Me-Ph 407.519 408 yl) 298 FCH2OCH2Ph 2,3-di-F-Ph 395.367 396 299 L Benzothien-2-yl 2,3-di-F-Ph407.403 408 300 F CH2OMe 3-Me-Ph 297.316 298 301 F CH2Ph 3-Me-Ph 343.388344 302 F CH2OCH2Ph 3-Me-Ph 373.414 374 303 F CH2OPh 3-Me-Ph 359.387 360304 L 4-[CH2(4-Et-Piperazin-1- 2,3-di-F-Ph 477.517 478 yl)]-Ph 305 L(CH2)3(4-(cyclo-pentyl)- 2,3-di-F-Ph 469.537 470 Piperazin-1-yl) 306 L(CH2)3(4-(CH2cyclo- 2,3-di-F-Ph 497.591 498 hexyl)-Piperazin-1-yl) 307 FCH2-(4-MeO-Ph) 3-Me-Ph 373.414 374

1. A compound of formula (I),

or a salt thereof, wherein; Y is N; R¹ is unsubstituted or substitutedalkyl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted alkenyl, unsubstituted or substituted cycloalkenyl,unsubstituted or substituted aryl, aralkyl wherein the aryl and thealkyl moieties may each independently be unsubstituted or substituted,aralkenyl wherein the aryl and alkenyl moieties may each independentlybe unsubstituted or substituted, unsubstituted or substitutedheterocyclyl, or heterocyclylalkyl wherein the heterocyclyl and thealkyl moieties may each independently be unsubstituted or substituted;and R² is unsubstituted or substituted aryl or unsubstituted orsubstituted heteroaryl.
 2. A compound of formula (I) as claimed in claim1, wherein: Y is N; R¹ is unsubstituted or substituted alkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedalkenyl, unsubstituted or substituted aryl, aralkyl wherein the aryl andthe alkyl moieties may each independently be unsubstituted orsubstituted, aralkenyl wherein the aryl and alkenyl moieties may eachindependently be unsubstituted or substituted, unsubstituted orsubstituted heterocyclyl and heterocyclylalkyl wherein the heterocyclyland the alkyl moieties may each independently be unsubstituted orsubstituted; and R² is as defined in claim
 1. 3. A compound of formula(I) as claimed in claim 1, wherein: Y is N; R¹ is trifluoromethyl,2,2,2-trifluoroethyl, methyl, ethyl, n-propyl, n-butyl, 2-butyl,n-pentyl, 3-pentyl, n-hexyl, methoxymethyl, 2-carboxyethyl, n-propenyl,iso-butenyl, styryl, phenyl, 2-furyl, 2-thienyl, benzyl, phenylethyl,3-(N,N-dimethylamino)propyl, pyridin-4-yl, 3-(piperidin-1-yl)propyl,3-(4-ethylpiperazin-1-yl)propyl, 3-(morpholin-1-yl)propyl,1,3-benzodioxolan-5-yl, N-methylpiperidin-4-yl, iso-propyl,pyridin-3-ylmethyl, α,α-dimethylbenzyl,3-(meso-3,5-dimethylmorpholin-4-yl)propyl, 4-(1-pyridinium)butyl bromidesalt, 2-(3-pyridinyl)ethyl, tert-butyl, phenoxymethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4-dimethylaminobenzyl,4-(dimethylaminomethyl)benzyl, methoxyethoxymethyl,2,2,2-trifluoroethoxymethyl, 3-dimethylaminophenoxymethyl,(1-methylpiperidin-4-yl)methyl, (1-ethylpiperidin-4-yl)methyl,(1-phenylpiperidin-4-yl)methyl, (1-benzylpiperidin-4-yl)methyl,(1-(4-fluorobenzyl)piperidin-4-yl)methyl,(1-(phenoxyethyl)piperidin-4-yl)methyl, 4-fluorophenethyl,(6-methylpyridn-3-yl)ethyl, methoxyethyl, 3-(N,N-diethylamino)propyl,N-methoxyethyl(N-methyl)aminopropyl, di-(N-methoxyethyl)aminopropyl,3-(1,1-dioxo-1-thiomorpholin-4-yl)propyl, 3-(pyrrolidin-1-yl)propyl,3-(4-benzylpiperazin-1-yl)propyl,3-(4-(4-chlorophenoxy)piperidin-1-yl)propyl,3-(4-methanesulfonylpiperazin-1-yl)propyl, 4-(N,N-diethylamino)butyl,4-(piperidin-1-yl)butyl, piperidin-4-yl, 1-ethylpiperidin-4-yl,1-benzylpiperidin-4-yl, 1-(4-chlorobenzyl)piperidin-4-yl,1-(4-fluorobenzyl)piperidin-4-yl, 1-(methoxyethyl)piperidin-4-yl,1-(phenoxyethyl)piperidin-4-yl, 1-(4-chlorophenoxyethyl)piperidin-4-yl,1-phenylpiperidin-4-yl, 1-benzylpyrrolidin-3-yl, trans-phenethenyl,trans-4-fluorophenethenyl, 4-fluorophenyl, 4-dimethylaminophenyl,2,4,6-trimethylphenyl, 4-(diethylaminomethyl)phenyl,4-(piperidin-1-ylmethyl)phenyl, 4-(pyrolidin-1-ylmethyl)phenyl,4-(thiomorpholin-4-ylmethyl)phenyl, 2,3-dihydrobenzofuran-5-yl,3-(4-(2-phenylethyl)piperazin-1-yl)propyl,3-(4-cyclohexylmethylpiperazin-1-yl)propyl,3-(4-cyclopentylpiperazin-1-yl)propyl,3-(4-iso-propylpiperazin-1-yl)propyl, 3-(4-phenylpiperazin-1-yl)propyl,4-(4-ethylpiperazin-1-yl)butyl, 3-(piperidin-1-ylmethyl)phenyl,4-(diethylaminomethyl)phenyl, 4-(4-ethylpiperazin-1-ylmethyl)phenyl,benzothien-2-yl, 4-methoxybenzyl or benzyloxymethyl. R² is as defined inclaim
 1. 4. A compound of formula (I) as defined in claim 1, wherein: Yis N; R¹ is as defined in claim 1; and R² is phenyl, pyridin-3-yl,pyridin-4-yl, 2-thienyl, 2-benzyloxyphenyl, 2-chlorophenyl,2-fluorophenyl, 2-methylphenyl, 2-methoxypyrid-3-yl, 2-methoxyphenyl,3,4-methylenedioxyphenyl, 3,5-dichlorophenyl, 3-acetamidophenyl,3-trifluoromethylphenyl, 3-chlorophenyl, 3-fluorophenyl, furan-3-yl,3-methoxyphenyl, 3-nitrophenyl, 3-thienyl, 4-trifluoromethylphenyl,4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl,4-trifluoromethoxyphenyl, indol-5-yl, 4-methoxypyridin-3-yl,2-chloro-3-fluorophenyl, 2,3-difluorophenyl, 2,3,6-trifluorophenyl,3-methylphenyl, pyridin-2-yl, quinolin-3-yl, 2-formylphenyl,3-formylphenyl, 3-methoxycarbonylphenyl, 3-carboxyphenyl, 3-cyanophenyl,2-[(morpholin-4-yl)methyl]phenyl, 3-[(morpholin-4-yl)methyl]phenyl,4-[(morpholin-4-yl)methyl]phenyl, 2-[2-(morpholin-4-yl)ethyl]phenyl,3-[2-(morpholin-4-yl)ethyl]phenyl, 4-[2-(morpholin-4-yl)ethyl]phenyl,3-hydoxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl,2-(dimethylaminoethoxy)phenyl, 3-(dimethylaminoethoxy)phenyl,4-(dimethylaminoethoxy)phenyl, 2-(3-dimethylaminopropoxy)phenyl,3-(3-dimethylaminopropoxy)phenyl, 4-(3-dimethylaminopropoxy)phenyl,2-[(morpholin-4-yl)ethoxy]phenyl, 3-[(morpholin-4-yl)ethoxy]phenyl,4-[(morpholin-4-yl)ethoxy]phenyl, 2-[3-(morpholin-4-yl)propoxy]phenyl,3-[3-(morpholin-4-yl)propoxy]phenyl,4-[3-(morpholin-4-yl)propoxy]phenyl, 1,3-benzodioxolan-5-yl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, 3-chloro-4-fluorophenyl, 2,5-dichlorophenyl,2,4-dichlorophenyl., 2,6-dichlorophenyl, 2,3,5-trifluorophenyl,2,3,4-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl,3,4,5-trifluorophenyl, 3-dimethylaminophenyl, 2-chloropyridin-3-yl,6-chloropyridin-3-yl, 2-chloro-5-methylpyridin-3-yl,2-chloro-4,5-dimethylpyridin-3-yl, 2,5-dimethylpyridin-3-yl,2-(t-butoxycarbonylamino)pyridin-3-yl, 2-(cyanomethyl)pyridin-3-yl,6-aminopyridin-3-yl, 6-(pyrrol-1-yl)pyridin-3-yl, 6-ureidopyridin-3-yl,5-phenylpyridin-3-yl, 2-amino-5-methylpyridin-3-yl,2-methyl-6-aminopyridin-3-yl, 5-methyl-6-aminopyridin-3-yl,5-methyl-6-(3-hydroxypropylamino)pyridin-3-yl,5-methyl-6-[3-(formylamino)propylamino]pyridin-3-yl,5-(piperidin-1-yl)pyridin-3-yl, 5-aminocarbonylpyridin-3-yl,5-(methoxycarbonylmethylcarbonyl)pyridin-3-yl,5-ethoxycarbonylpyridin-3-yl, 5-methoxypyridin-3-yl,4-methylpyridin-3-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrazin-2-yl,naphthalen-1-yl, furan-2-yl, biphenyl-4-yl, or benzo[b]thiophen-3-yl. 5.A compound of formula (I) as claimed in claim 1, wherein: Y is N; R¹ ismethyl, n-propyl, iso-propyl, cyclopropyl, cyclopentyl, benzyl,3-(N,N-dimethylamino)propyl, 3-(morpholin-4-yl)propyl,4-dimethylaminobenzyl, 4-(dimethylaminomethyl)benzyl, methoxymethyl,methoxyethoxymethyl, 2,2,2-trifluoroethoxymethyl, phenoxymethyl,3-dimethylaminophenoxymethyl, (1-methylpiperidin-4-yl)methyl,(1-ethylpiperidin-4-yl)methyl, (1-phenylpiperidin-4-yl)methyl,(1-benzylpiperidin-4-yl)methyl,(1-(4-fluorobenzyl)piperidin-4-yl)methyl,(1-(phenoxyethyl)piperidin-4-yl)methyl, phenethyl, 4-flurophenethyl,(6-methylpyridn-3-yl)ethyl, methoxyethyl, 3-(N,N-diethylamino)propyl,N-methoxyethyl(N-methyl)aminopropyl, di-(N-methoxyethyl)aminopropyl,3-(1,1-dioxo-1-thiomorpholin-4-yl)propyl, 3-(piperidin-1-yl)propyl,3-(pyrolidin-1-yl)propyl, 3-(4-ethylpiperazin-1-yl)propyl,3-(4-benzylpiperazin-1-yl)propyl,3-(4-(4-chlorophenoxy)piperidin-1-yl)propyl,3-(4-methanesulfonylpiperazin-1-yl)propyl, 4-(N,N-diethylamino)butyl,4-(piperidin-1-yl)butyl, piperidin-4-yl, 1-methylpiperidin-4-yl,1-ethylpiperidin-4-yl, 1-benzylpiperidin-4-yl,1-(4-chlorobenzyl)piperidin-4-yl, 1-(4-fluorobenzyl)piperidin-4-yl,1-(methoxyethyl)piperidin-4-yl, 1-(phenoxyethyl)piperidin-4-yl,1-(4-chlorophenoxyethyl)piperidin-4-yl, 1-phenylpiperidin-4-yl,1-benzylpyrolidin-3-yl, trans-phenethenyl, trans-4-fluorophenethenyl,phenyl, 4-flurophenyl, 4-dimethylaminopneyl, 2,4,6-trimethylphenyl,4-(diethylaminomethyl)phenyl, 4-(piperidin-1-ylmethyl)phenyl,4-(pyrolidin-1-ylmethyl)phenyl, 4(thiomorpholin-4-ylmethyl)phenyl,2,3-dihydrobenzofiuran-5-yl, 3-(4-(2-phenylethyl)piperazin-1-yl)propyl,3-(4-cyclohexylmethylpiperazin-1-yl)propyl,3-(4-cyclopentylpiperazin-1-yl)propyl,3-(4-iso-propylpiperazin-1-yl)propyl, 3-(4-phenylpiperazin-1-yl)propyl,4-(4-ethylpiperazin-1-yl)butyl, 3-(piperidin-1-ylmethyl)phenyl,4-(diethylaminomethyl)phenyl, 4-(4-ethylpiperazin-1-ylmethyl)phenyl,benzothien-2-yl, 4-methoxybenzyl or benzyloxymethyl; and R² is phenyl,2-chlorophenyl, 2-chloro-3-fluorophenyl, 2,3-duorophenyl,2,3,6-trifluorophenyl, 3-methylphenyl, pyridin-2-yl, pyridin-3-yl orquinolin-3-yl.
 6. A pharmaceutical composition which comprises acompound of formula (I) as claimed in claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.
 7. Aprocess for the preparation of a compound of formula (I) as claimed inclaim 1 or a salt thereof, which process comprises reaction of acompound of formula (II),

wherein; Y and R² are as defined in formula (I), with a compound offormula (III)

 wherein; R¹ is as defined in formula (I) and X is a leaving group, andthereafter, if required, carrying out one or more of the followingoptional steps: (i) converting a compound of formula (I) to a furthercompound of formula (I); (ii) removing any necessary protecting group;(iii) preparing an appropriate derivative of the compound so formed. 8.A process for the preparation of a compound of formula (I) as claimed inclaim 1, which process comprises reacting a compound of formula (IV),

with a nucleophile.
 9. A method for the treatment of diabetes whichmethod comprises the administration of a pharmaceutically effective,non-toxic amount of a compound of formula (I) as claimed in claim 1 or apharmaceutically acceptable salt thereof.
 10. A method for the treatmentof diabetes which method comprises the administration of apharmaceutically effective, non-toxic amount of a compound of claim 2 ora pharmaceutically acceptable salt thereof.
 11. A method for thetreatment of diabetes which method comprises the administration of apharmaceutically effective, non-toxic amount of a compound of claim 3 ora pharmaceutically acceptable salt thereof.
 12. A method for thetreatment of diabetes which method comprises the administration of apharmaceutically effective, non-toxic amount of a compound of claim 4 ora pharmaceutically acceptable salt thereof.
 13. A method for thetreatment of diabetes which method comprises the administration of apharmaceutically effective, non-toxic amount of a compound of claim 5 ora pharmaceutically acceptable salt thereof.
 14. A method for thetreatment of diabetes which method comprises the administration of acomposition of claim 6.